Cheung J

General

Full name : Cheung Jonah

First name : Jonah

Mail : New York Structural Biology Center\; NYCOMPS\; 89 Convent Avenue\; New York\; 10027

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Country : USA

Email : jcheung@nysbc.org

Phone : +12129390660 x9375

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References (16)

Title : Structural and Biochemical Insights into the Inhibition of Human Acetylcholinesterase by G-Series Nerve Agents and Subsequent Reactivation by HI-6 - McGuire_2021_Chem.Res.Toxicol_34_804
Author(s) : McGuire JR , Bester SM , Guelta MA , Cheung J , Langley C , Winemiller MD , Bae SY , Funk V , Myslinski JM , Pegan SD , Height JJ
Ref : Chemical Research in Toxicology , 34 :804 , 2021
Abstract : The recent use of organophosphate nerve agents in Syria, Malaysia, Russia, and the United Kingdom has reinforced the potential threat of their intentional release. These agents act through their ability to inhibit human acetylcholinesterase (hAChE; E.C. 3.1.1.7), an enzyme vital for survival. The toxicity of hAChE inhibition via G-series nerve agents has been demonstrated to vary widely depending on the G-agent used. To gain insight into this issue, the structures of hAChE inhibited by tabun, sarin, cyclosarin, soman, and GP were obtained along with the inhibition kinetics for these agents. Through this information, the role of hAChE active site plasticity in agent selectivity is revealed. With reports indicating that the efficacy of reactivators can vary based on the nerve agent inhibiting hAChE, human recombinatorially expressed hAChE was utilized to define these variations for HI-6 among various G-agents. To identify the structural underpinnings of this phenomenon, the structures of tabun, sarin, and soman-inhibited hAChE in complex with HI-6 were determined. This revealed how the presence of G-agent adducts impacts reactivator access and placement within the active site. These insights will contribute toward a path of next-generation reactivators and an improved understanding of the innate issues with the current reactivators.
ESTHER : McGuire_2021_Chem.Res.Toxicol_34_804
PubMedSearch : McGuire_2021_Chem.Res.Toxicol_34_804
PubMedID: 33538594
Gene_locus related to this paper: human-ACHE

Title : Rate-limiting step in the decarbamoylation of acetylcholinesterases with large carbamoyl groups - Rosenberry_2019_Chem.Biol.Interact_13ChEPon_
Author(s) : Rosenberry TL , Cheung J
Ref : Chemico-Biological Interactions , : , 2019
Abstract : Carbamates are esters of substituted carbamic acids that react with acetylcholinesterase (AChE) by initially transferring the carbamoyl group to a serine residue in the enzyme active site accompanied by loss of the carbamate leaving group followed by hydrolysis of the carbamoyl enzyme. This hydrolysis, or decarbamoylation, is relatively slow, and half-lives of carbamoylated AChEs range from 4min to more than 30 days. Therefore, carbamates are effective AChE inhibitors that have been developed as insecticides and as therapeutic agents. In this report, we review recent data showing that decarbamoylation rate constants are independent of the ester leaving group for a series of carbamic acid esters with the same carbamoyl group and that decarbamoylation rate constants decreased by 800-fold when the alkyl substituents on the carbamoyl group increased in size from N-monomethyl- to N,N-diethyl-. We also review data showing that solvent deuterium oxide isotope effects for decarbamoylation decreased from 2.8 for N-monomethylcarbamoyl AChE to 1.1 for N,N-diethylcarbamoyl AChE, indicating a shift in the rate-limiting step from general acid-base catalysis to a likely conformational change in the distorted active site in N,N-diethylcarbamoyl AChE. The nature of such a conformational change is suggested from X-ray crystal structures of AChE phosphorylated by paraoxon.
ESTHER : Rosenberry_2019_Chem.Biol.Interact_13ChEPon_
PubMedSearch : Rosenberry_2019_Chem.Biol.Interact_13ChEPon_
PubMedID: 31175846

Title : beta2-Adrenergic receptor agonists ameliorate the adverse effect of long-term pyridostigmine on neuromuscular junction structure - Vanhaesebrouck_2019_Brain_142_3713
Author(s) : Vanhaesebrouck AE , Webster R , Maxwell S , Rodriguez Cruz PM , Cossins J , Wickens J , Liu WW , Cetin H , Cheung J , Ramjattan H , Palace J , Beeson D
Ref : Brain , 142 :3713 , 2019
Abstract : Acetylcholine receptor deficiency is the most common form of the congenital myasthenic syndromes, a heterogeneous collection of genetic disorders of neuromuscular transmission characterized by fatiguable muscle weakness. Most patients with acetylcholine receptor deficiency respond well to acetylcholinesterase inhibitors; however, in some cases the efficacy of acetylcholinesterase inhibitors diminishes over time. Patients with acetylcholine receptor deficiency can also benefit from the addition of a beta2-adrenergic receptor agonist to their medication. The working mechanism of beta2-adrenergic agonists in myasthenic patients is not fully understood. Here, we report the long-term follow-up for the addition of beta2-adrenergic agonists for a cohort of patients with acetylcholine receptor deficiency on anticholinesterase medication that demonstrates a sustained quantitative improvement. Coincidently we used a disease model to mirror the treatment of acetylcholine receptor deficiency, and demonstrate improved muscle fatigue, improved neuromuscular transmission and improved synaptic structure resulting from the addition of the beta2-adrenergic agonist salbutamol to the anticholinesterase medication pyridostigmine. Following an initial improvement in muscle fatiguability, a gradual decline in the effect of pyridostigmine was observed in mice treated with pyridostigmine alone (P < 0.001). Combination therapy with pyridostigmine and salbutamol counteracted this decline (P < 0.001). Studies of compound muscle action potential decrement at high nerve stimulation frequencies (P < 0.05) and miniature end-plate potential amplitude analysis (P < 0.01) showed an improvement in mice following combination therapy, compared to pyridostigmine monotherapy. Pyridostigmine alone reduced postsynaptic areas (P < 0.001) and postsynaptic folding (P < 0.01). Combination therapy increased postsynaptic area (P < 0.001) and promoted the formation of postsynaptic junctional folds (P < 0.001), in particular in fast-twitch muscles. In conclusion, we demonstrate for the first time how the improvement seen in patients from adding salbutamol to their medication can be explained in an experimental model of acetylcholine receptor deficiency, the most common form of congenital myasthenic syndrome. Salbutamol enhances neuromuscular junction synaptic structure by counteracting the detrimental effects of long-term acetylcholinesterase inhibitors on the postsynaptic neuromuscular junction. The results have implications for both autoimmune and genetic myasthenias where anticholinesterase medication is a standard treatment.
ESTHER : Vanhaesebrouck_2019_Brain_142_3713
PubMedSearch : Vanhaesebrouck_2019_Brain_142_3713
PubMedID: 31633155

Title : The structural and biochemical impacts of monomerizing human acetylcholinesterase - Bester_2019_Protein.Sci_28_1106
Author(s) : Bester SM , Adipietro KA , Funk VL , Myslinski JM , Keul ND , Cheung J , Wilder PT , Wood ZA , Weber DJ , Height JJ , Pegan SD
Ref : Protein Science , 28 :1106 , 2019
Abstract : Serving a critical role in neurotransmission, human acetylcholinesterase (hAChE) is the target of organophosphate nerve agents. Hence, there is an active interest in studying the mechanism of inhibition and recovery of enzymatic activity, which could lead to better countermeasures against nerve agents. As hAChE is found in different oligomeric assemblies, certain approaches to studying it have been problematic. Herein, we examine the biochemical and structural impact of monomerizing hAChE by using two mutations: L380R/F535K. The activities of monomeric hAChE L380R/F535K and dimeric hAChE were determined to be comparable utilizing a modified Ellman's assay. To investigate the influence of subunit-subunit interactions on the structure of hAChE, a 2.1 A X-ray crystallographic structure was determined. Apart from minor shifts along the dimer interface, the overall structure of the hAChE L380R/F535K mutant is similar to that of dimeric hAChE. To probe whether the plasticity of the active site was overtly impacted by monomerizing hAChE, the kinetic constants of (PR/S ) - VX (ethyl({2-[bis(propan-2-yl)amino]ethyl}sulfanyl)(methyl)phosphinate) inhibition and subsequent rescue of hAChE L380R/F535K activity with HI-6 (1-(2'-hydroxyiminomethyl-1'-pyridinium)-3-(4'-carbamoyl-1-pyridinium)) were determined and found to be comparable to those of dimeric hAChE. Thus, hAChE L380R/F535K could be used as a substitute for dimeric hAChE when experimentally probing the ability of the hAChE active site to accommodate future nerve agent threats or judge the ability of new therapeutics to access the active site.
ESTHER : Bester_2019_Protein.Sci_28_1106
PubMedSearch : Bester_2019_Protein.Sci_28_1106
PubMedID: 30993792
Gene_locus related to this paper: human-ACHE

Title : Structure of the G119S Mutant Acetylcholinesterase of the Malaria Vector Anopheles gambiae Reveals Basis of Insecticide Resistance - Cheung_2018_Structure_26_130
Author(s) : Cheung J , Mahmood A , Kalathur R , Liu L , Carlier PR
Ref : Structure , 26 :130 , 2018
Abstract : Malaria is a devastating disease in sub-Saharan Africa and is transmitted by the mosquito Anopheles gambiae. While indoor residual spraying of anticholinesterase insecticides has been useful in controlling the spread of malaria, widespread application of these compounds has led to the rise of an insecticide-resistant mosquito strain that harbors a G119S mutation in the nervous system target enzyme acetylcholinesterase. We demonstrate the atomic basis of insecticide resistance through structure determination of the G119S mutant acetylcholinesterase of An. gambiae in the ligand-free state and bound to a potent difluoromethyl ketone inhibitor. These structures reveal specific features within the active-site gorge distinct from human acetylcholinesterase, including an open channel at the base of the gorge, and provide a means for improving species selectivity in the rational design of improved insecticides for malaria vector control.
ESTHER : Cheung_2018_Structure_26_130
PubMedSearch : Cheung_2018_Structure_26_130
PubMedID: 29276037
Gene_locus related to this paper: anoga-ACHE1

Title : A manually annotated Actinidia chinensis var. chinensis (kiwifruit) genome highlights the challenges associated with draft genomes and gene prediction in plants - Pilkington_2018_BMC.Genomics_19_257
Author(s) : Pilkington SM , Crowhurst R , Hilario E , Nardozza S , Fraser L , Peng Y , Gunaseelan K , Simpson R , Tahir J , Deroles SC , Templeton K , Luo Z , Davy M , Cheng C , McNeilage M , Scaglione D , Liu Y , Zhang Q , Datson P , De Silva N , Gardiner SE , Bassett H , Chagne D , McCallum J , Dzierzon H , Deng C , Wang YY , Barron L , Manako K , Bowen J , Foster TM , Erridge ZA , Tiffin H , Waite CN , Davies KM , Grierson EP , Laing WA , Kirk R , Chen X , Wood M , Montefiori M , Brummell DA , Schwinn KE , Catanach A , Fullerton C , Li D , Meiyalaghan S , Nieuwenhuizen N , Read N , Prakash R , Hunter D , Zhang H , McKenzie M , Knabel M , Harris A , Allan AC , Gleave A , Chen A , Janssen BJ , Plunkett B , Ampomah-Dwamena C , Voogd C , Leif D , Lafferty D , Souleyre EJF , Varkonyi-Gasic E , Gambi F , Hanley J , Yao JL , Cheung J , David KM , Warren B , Marsh K , Snowden KC , Lin-Wang K , Brian L , Martinez-Sanchez M , Wang M , Ileperuma N , Macnee N , Campin R , McAtee P , Drummond RSM , Espley RV , Ireland HS , Wu R , Atkinson RG , Karunairetnam S , Bulley S , Chunkath S , Hanley Z , Storey R , Thrimawithana AH , Thomson S , David C , Testolin R , Huang H , Hellens RP , Schaffer RJ
Ref : BMC Genomics , 19 :257 , 2018
Abstract : BACKGROUND: Most published genome sequences are drafts, and most are dominated by computational gene prediction. Draft genomes typically incorporate considerable sequence data that are not assigned to chromosomes, and predicted genes without quality confidence measures. The current Actinidia chinensis (kiwifruit) 'Hongyang' draft genome has 164 Mb of sequences unassigned to pseudo-chromosomes, and omissions have been identified in the gene models. RESULTS: A second genome of an A. chinensis (genotype Red5) was fully sequenced. This new sequence resulted in a 554.0 Mb assembly with all but 6 Mb assigned to pseudo-chromosomes. Pseudo-chromosomal comparisons showed a considerable number of translocation events have occurred following a whole genome duplication (WGD) event some consistent with centromeric Robertsonian-like translocations. RNA sequencing data from 12 tissues and ab initio analysis informed a genome-wide manual annotation, using the WebApollo tool. In total, 33,044 gene loci represented by 33,123 isoforms were identified, named and tagged for quality of evidential support. Of these 3114 (9.4%) were identical to a protein within 'Hongyang' The Kiwifruit Information Resource (KIR v2). Some proportion of the differences will be varietal polymorphisms. However, as most computationally predicted Red5 models required manual re-annotation this proportion is expected to be small. The quality of the new gene models was tested by fully sequencing 550 cloned 'Hort16A' cDNAs and comparing with the predicted protein models for Red5 and both the original 'Hongyang' assembly and the revised annotation from KIR v2. Only 48.9% and 63.5% of the cDNAs had a match with 90% identity or better to the original and revised 'Hongyang' annotation, respectively, compared with 90.9% to the Red5 models. CONCLUSIONS: Our study highlights the need to take a cautious approach to draft genomes and computationally predicted genes. Our use of the manual annotation tool WebApollo facilitated manual checking and correction of gene models enabling improvement of computational prediction. This utility was especially relevant for certain types of gene families such as the EXPANSIN like genes. Finally, this high quality gene set will supply the kiwifruit and general plant community with a new tool for genomics and other comparative analysis.
ESTHER : Pilkington_2018_BMC.Genomics_19_257
PubMedSearch : Pilkington_2018_BMC.Genomics_19_257
PubMedID: 29661190
Gene_locus related to this paper: actde-CXE3 , actde-CXE5 , actch-a0a2r6p9v4 , actch-a0a2r6phk8 , actch-a0a2r6pty2 , actch-q0zpu6 , actcc-a0a2r6q553 , actcc-a0a2r6quq2 , actcc-a0a2r6q2m9 , actcc-a0a2r6q2n7 , actcc-a0a2r6ru97 , actcc-a0a2r6r3e8 , actcc-a0a2r6qy24 , actcc-a0a2r6pzy5 , actcc-a0a2r6p5n3 , actcc-a0a2r6qdp0 , actcc-a0a2r6qgs9

Title : Structural Insights of Stereospecific Inhibition of Human Acetylcholinesterase by VX and Subsequent Reactivation by HI-6 - Bester_2018_Chem.Res.Toxicol_31_1405
Author(s) : Bester SM , Guelta MA , Cheung J , Winemiller MD , Bae SY , Myslinski J , Pegan SD , Height JJ
Ref : Chemical Research in Toxicology , 31 :1405 , 2018
Abstract : Over 50 years ago, the toxicity of irreversible organophosphate inhibitors targeting human acetylcholinesterase (hAChE) was observed to be stereospecific. The therapeutic reversal of hAChE inhibition by reactivators has also been shown to depend on the stereochemistry of the inhibitor. To gain clarity on the mechanism of stereospecific inhibition, the X-ray crystallographic structures of hAChE inhibited by a racemic mixture of VX (P R/S) and its enantiomers were obtained. Beyond identifying hAChE structural features that lend themselves to stereospecific inhibition, structures of the reactivator HI-6 bound to hAChE inhibited by VX enantiomers of varying toxicity, or in its uninhibited state, were obtained. Comparison of hAChE in these pre-reactivation and post-reactivation states along with enzymatic data reveals the potential influence of unproductive reactivator poses on the efficacy of these types of therapeutics. The recognition of structural features related to hAChE's stereospecificity toward VX shed light on the molecular influences of toxicity and their effect on reactivators. In addition to providing a better understanding of the innate issues with current reactivators, an avenue for improvement of reactivators is envisioned.
ESTHER : Bester_2018_Chem.Res.Toxicol_31_1405
PubMedSearch : Bester_2018_Chem.Res.Toxicol_31_1405
PubMedID: 30462502
Gene_locus related to this paper: human-ACHE

Title : Structures of paraoxon-inhibited human acetylcholinesterase reveal perturbations of the acyl loop and the dimer interface - Franklin_2016_Proteins_84_1246
Author(s) : Franklin MC , Rudolph MJ , Ginter C , Cassidy MS , Cheung J
Ref : Proteins , 84 :1246 , 2016
Abstract : Irreversible inhibition of the essential nervous system enzyme acetylcholinesterase by organophosphate nerve agents and pesticides may quickly lead to death. Oxime reactivators currently used as antidotes are generally less effective against pesticide exposure than nerve agent exposure, and pesticide exposure constitutes the majority of cases of organophosphate poisoning in the world. The current lack of published structural data specific to human acetylcholinesterase organophosphate-inhibited and oxime-bound states hinders development of effective medical treatments. We have solved structures of human acetylcholinesterase in different states in complex with the organophosphate insecticide, paraoxon, and oximes. Reaction with paraoxon results in a highly perturbed acyl loop that causes a narrowing of the gorge in the peripheral site that may impede entry of reactivators. This appears characteristic of acetylcholinesterase inhibition by organophosphate insecticides but not nerve agents. Additional changes seen at the dimer interface are novel and provide further examples of the disruptive effect of paraoxon. Ternary structures of paraoxon-inhibited human acetylcholinesterase in complex with the oximes HI6 and 2-PAM reveals relatively poor positioning for reactivation. This study provides a structural foundation for improved reactivator design for the treatment of organophosphate intoxication. Proteins 2016; 84:1246-1256. (c) 2016 Wiley Periodicals, Inc.
ESTHER : Franklin_2016_Proteins_84_1246
PubMedSearch : Franklin_2016_Proteins_84_1246
PubMedID: 27191504
Gene_locus related to this paper: human-ACHE

Title : Hopeahainol A binds reversibly at the acetylcholinesterase (AChE) peripheral site and inhibits enzyme activity with a novel higher order concentration dependence - Rosenberry_2016_Chem.Biol.Interact_259_78
Author(s) : Rosenberry TL , Martin PK , Nix AJ , Wildman SA , Cheung J , Snyder SA , Tan RX
Ref : Chemico-Biological Interactions , 259 :78 , 2016
Abstract : Natural product inhibitors of AChE are of interest both because they offer promise as inexpensive drugs for symptomatic relief in Alzheimer's disease and because they may provide insights into the structural features of the AChE catalytic site. Hopeahainol A is an uncharged polyphenol AChE inhibitor from the stem bark of H. hainanensis with a constrained, partially dearomatized bicyclic core. Molecular modeling indicates that hopeahainol A binds at the entrance of the long but narrow AChE active site gorge because it is too bulky to be accommodated within the gorge without severe distortion of the gorge as depicted in AChE crystal structures. We conducted inhibitor competition experiments in which AChE inhibition was measured with hopeahainol A together with either edrophonium (which binds at the base of the gorge) or thioflavin T (which binds to the peripheral or P-site near the gorge mouth). The results agreed with the molecular modeling and indicated that hopeahainol A at lower concentrations (<200 muM) bound only to the P-site, as hopeahainol A and thioflavin T were unable to form a ternary complex with AChE while hopeahainol A and edrophonium did form a ternary complex with essentially no competition between them. Inhibition increased to a striking extent at higher concentrations of hopeahainol A, with plots analogous to classic Dixon plots showing a dependence on hopeahainol A concentrations to the third- or fourth order. The inhibition at higher hopeahainol A concentrations was completely reversed on dilution and blocked by bound edrophonium. We hypothesize that bound hopeahainol A induces conformational changes in the AChE active site that allow binding of additional hopeahainol A molecules, a phenomenon that would be unprecedented for a reversible inhibitor that apparently forms no covalent bonds with AChE.
ESTHER : Rosenberry_2016_Chem.Biol.Interact_259_78
PubMedSearch : Rosenberry_2016_Chem.Biol.Interact_259_78
PubMedID: 27297626

Title : Structural genomics for drug design against the pathogen Coxiella burnetii - Franklin_2015_Proteins_83_2124
Author(s) : Franklin MC , Cheung J , Rudolph MJ , Burshteyn F , Cassidy M , Gary E , Hillerich B , Yao ZK , Carlier PR , Totrov M , Love JD
Ref : Proteins , 83 :2124 , 2015
Abstract : Coxiella burnetii is a highly infectious bacterium and potential agent of bioterrorism. However, it has not been studied as extensively as other biological agents, and very few of its proteins have been structurally characterized. To address this situation, we undertook a study of critical metabolic enzymes in C. burnetii that have great potential as drug targets. We used high-throughput techniques to produce novel crystal structures of 48 of these proteins. We selected one protein, C. burnetii dihydrofolate reductase (CbDHFR), for additional work to demonstrate the value of these structures for structure-based drug design. This enzyme's structure reveals a feature in the substrate binding groove that is different between CbDHFR and human dihydrofolate reductase (hDHFR). We then identified a compound by in silico screening that exploits this binding groove difference, and demonstrated that this compound inhibits CbDHFR with at least 25-fold greater potency than hDHFR. Since this binding groove feature is shared by many other prokaryotes, the compound identified could form the basis of a novel antibacterial agent effective against a broad spectrum of pathogenic bacteria. Proteins 2015; 83:2124-2136. (c) 2015 Wiley Periodicals, Inc.
ESTHER : Franklin_2015_Proteins_83_2124
PubMedSearch : Franklin_2015_Proteins_83_2124
PubMedID: 26033498
Gene_locus related to this paper: coxbu-CBU1769

Title : Acetylcholinesterase complexes with the natural product inhibitors dihydrotanshinone I and territrem B: binding site assignment from inhibitor competition and validation through crystal structure determination - Cheung_2014_J.Mol.Neurosci_53_506
Author(s) : Cheung J , Beri V , Shiomi K , Rosenberry TL
Ref : Journal of Molecular Neuroscience , 53 :506 , 2014
Abstract : Acetylcholinesterase (AChE) is a critical enzyme that regulates neurotransmission by degrading the neurotransmitter acetylcholine in synapses of the nervous system. It is an important target for both therapeutic drugs that treat Alzheimer's disease and organophosphate (OP) chemical warfare agents that cripple the nervous system and cause death through paralysis. We are exploring a strategy to design compounds that bind tightly at or near a peripheral or P-site near the mouth of the AChE active site gorge and exclude OPs from the active site while interfering minimally with the passage of acetylcholine. However, to target the AChE P-site, much more information must be gathered about the structure-activity relationships of ligands that bind specifically to the P-site. Here, we review our recent reports on two uncharged, natural product inhibitors of AChE, dihydrotanshinone I and territrem B, that have relatively high affinities for the enzyme. We describe an inhibitor competition assay and comment on the structures of these inhibitors in complex with recombinant human acetylcholinesterase as determined by X-ray crystallography. Our results reveal that dihydrotanshinone I binding is specific to only the P-site, while territrem B binding spans the P-site and extends into the acylation or A-site at the base of the gorge.
ESTHER : Cheung_2014_J.Mol.Neurosci_53_506
PubMedSearch : Cheung_2014_J.Mol.Neurosci_53_506
PubMedID: 24573600

Title : The natural product dihydrotanshinone I provides a prototype for uncharged inhibitors that bind specifically to the acetylcholinesterase peripheral site with nanomolar affinity - Beri_2013_Biochemistry_52_7486
Author(s) : Beri V , Wildman SA , Shiomi K , Al-Rashid ZF , Cheung J , Rosenberry TL
Ref : Biochemistry , 52 :7486 , 2013
Abstract : Cholinergic synaptic transmission often requires extremely rapid hydrolysis of acetylcholine by acetylcholinesterase (AChE). AChE is inactivated by organophosphates (OPs) in chemical warfare nerve agents. The resulting accumulation of acetylcholine disrupts cholinergic synaptic transmission and can lead to death. A potential long-term strategy for preventing AChE inactivation by OPs is based on evidence that OPs must pass through a peripheral site or P-site near the mouth of the AChE active site gorge before reacting with a catalytic serine in an acylation site or A-site at the base of the gorge. An ultimate goal of this strategy is to design compounds that bind tightly at or near the P-site and exclude OPs from the active site while interfering minimally with the passage of acetylcholine. However, to target the AChE P-site with ligands and potential drugs that selectively restrict access, much more information must be gathered about the structure-activity relationships of ligands that bind specifically to the P-site. We apply here an inhibitor competition assay that can correctly determine whether an AChE inhibitor binds to the P-site, the A-site, or both sites. We have used this assay to examine three uncharged, natural product inhibitors of AChE, including aflatoxin B1, dihydrotanshinone I, and territrem B. The first two of these inhibitors are predicted by the competition assay to bind selectively to the P-site, while territrem B is predicted to span both the P- and A-sites. These predictions have recently been confirmed by X-ray crystallography. Dihydrotanshinone I, with an observed binding constant (KI) of 750 nM, provides a good lead compound for the development of high-affinity, uncharged inhibitors with specificity for the P-site.
ESTHER : Beri_2013_Biochemistry_52_7486
PubMedSearch : Beri_2013_Biochemistry_52_7486
PubMedID: 24040835

Title : Structures of Human Acetylcholinesterase Bound to Dihydrotanshinone I and Territrem B Show Peripheral Site Flexibility - Cheung_2013_ACS.Med.Chem.Lett_4_1091
Author(s) : Cheung J , Gary EN , Shiomi K , Rosenberry TL
Ref : ACS Med Chem Lett , 4 :1091 , 2013
Abstract : Acetylcholinesterase is a critical enzyme that regulates neurotransmission by degrading the neurotransmitter acetylcholine in synapses of the nervous system. It is an important target for both therapeutic drugs that treat Alzheimers disease and chemical warfare agents that cripple the nervous system and cause death through paralysis. The enzyme has both catalytic and peripheral sites to which inhibitors may bind. Structures of recombinant human acetylcholinesterase in complex with the natural product inhibitors dihydrotanshinone I and territrem B reveal dihydrotanshinone I binding that is specific to only the peripheral site and territrem B binding that spans both sites and distorts the protein backbone in the peripheral site. These inhibitors may function as important molecular templates for therapeutics used for treatment of disease and protection against nerve agents.
ESTHER : Cheung_2013_ACS.Med.Chem.Lett_4_1091
PubMedSearch : Cheung_2013_ACS.Med.Chem.Lett_4_1091
PubMedID: 24900610
Gene_locus related to this paper: human-ACHE

Title : Structures of human acetylcholinesterase in complex with pharmacologically important ligands - Cheung_2012_J.Med.Chem_55_10282
Author(s) : Cheung J , Rudolph MJ , Burshteyn F , Cassidy MS , Gary EN , Love J , Franklin MC , Height JJ
Ref : Journal of Medicinal Chemistry , 55 :10282 , 2012
Abstract : Human acetylcholinesterase (AChE) is a significant target for therapeutic drugs. Here we present high resolution crystal structures of human AChE, alone and in complexes with drug ligands; donepezil, an Alzheimer's disease drug, binds differently to human AChE than it does to Torpedo AChE. These crystals of human AChE provide a more accurate platform for further drug development than previously available.
ESTHER : Cheung_2012_J.Med.Chem_55_10282
PubMedSearch : Cheung_2012_J.Med.Chem_55_10282
PubMedID: 23035744
Gene_locus related to this paper: human-ACHE

Title : Crystal structure of a functional dimer of the PhoQ sensor domain - Cheung_2008_J.Biol.Chem_283_13762
Author(s) : Cheung J , Bingman CA , Reyngold M , Hendrickson WA , Waldburger CD
Ref : Journal of Biological Chemistry , 283 :13762 , 2008
Abstract : The PhoP-PhoQ two-component system is a well studied bacterial signaling system that regulates virulence and stress response. Catalytic activity of the histidine kinase sensor protein PhoQ is activated by low extracellular concentrations of divalent cations such as Mg2+, and subsequently the response regulator PhoP is activated in turn through a classic phosphotransfer pathway that is typical in such systems. The PhoQ sensor domains of enteric bacteria contain an acidic cluster of residues (EDDDDAE) that has been implicated in direct binding to divalent cations. We have determined crystal structures of the wild-type Escherichia coli PhoQ periplasmic sensor domain and of a mutant variant in which the acidic cluster was neutralized to conservative uncharged residues (QNNNNAQ). The PhoQ domain structure is similar to that of DcuS and CitA sensor domains, and this PhoQ-DcuS-CitA (PDC) sensor fold is seen to be distinct from the superficially similar PAS domain fold. Analysis of the wild-type structure reveals a dimer that allows for the formation of a salt bridge across the dimer interface between Arg-50' and Asp-179 and with nickel ions bound to aspartate residues in the acidic cluster. The physiological importance of the salt bridge to in vivo PhoQ function has been confirmed by mutagenesis. The mutant structure has an alternative, non-physiological dimeric association.
ESTHER : Cheung_2008_J.Biol.Chem_283_13762
PubMedSearch : Cheung_2008_J.Biol.Chem_283_13762
PubMedID: 18348979

Title : Identification of a novel lipase gene mutated in lpd mice with hypertriglyceridemia and associated with dyslipidemia in humans - Wen_2003_Hum.Mol.Genet_12_1131
Author(s) : Wen XY , Hegele RA , Wang J , Wang DY , Cheung J , Wilson M , Yahyapour M , Bai Y , Zhuang L , Skaug J , Young TK , Connelly PW , Koop BF , Tsui LC , Stewart AK
Ref : Hum Mol Genet , 12 :1131 , 2003
Abstract : Triglyceride (TG) metabolism is crucial for whole body and local energy homeostasis and accumulating evidence suggests an independent association between plasma TG concentration and increased atherosclerosis risk. We previously generated a mouse insertional mutation lpd (lipid defect) whose phenotype included elevated plasma TG and hepatic steatosis. Using shotgun sequencing (approximately 500 kb) and bioinformatics, we have now identified a novel lipase gene lpdl (lpd lipase) within the lpd locus, and demonstrate the genetic disruption of exon 10 of lpdl in the lpd mutant locus. lpdl is highly expressed in the testis and weakly expressed in the liver of 2-week old mice. Human LPDL cDNA was subsequently cloned, and was found to encode a 460AA protein with 71% protein sequence identity to mouse lpdl and approximately 35% identity to other known lipases. We next sequenced the human LPDL gene exons in hypertriglyceridemic subjects and normal controls, and identified seven SNPs within the gene exons and six SNPs in the adjacent introns. Two hypertriglyceridemic subjects were heterozygous for a rare DNA variant, namely 164G>A (C55Y), which was absent from 600 normal chromosomes. Two other coding SNPs were associated with variation in plasma HDL cholesterol in independent normolipidemic populations. Using bioinformatics, we identified another novel lipase designated LPDLR (for 'LPDL related lipase'), which had 44% protein sequence identity with LPDL. Together with the phospholipase gene PSPLA1, LPDL and LPDLR form a new lipase gene subfamily, which is characterized by shortened lid motif. Study of this lipase subfamily may identify novel molecular mechanisms for plasma and/or tissue TG metabolism.
ESTHER : Wen_2003_Hum.Mol.Genet_12_1131
PubMedSearch : Wen_2003_Hum.Mol.Genet_12_1131
PubMedID: 12719377
Gene_locus related to this paper: human-LIPI