Correy GJ


Full name : Correy Galen J

First name : Galen J

Mail : Research School of Chemistry, Australian National University, Canberra, ACT 2601

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Country : Australia

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References (7)

Title : Overcoming insecticide resistance through computational inhibitor design - Correy_2019_Proc.Natl.Acad.Sci.U.S.A_116_21012
Author(s) : Correy GJ , Zaidman D , Harmelin A , Carvalho S , Mabbitt PD , Calaora V , James PJ , Kotze AC , Jackson CJ , London N
Ref : Proc Natl Acad Sci U S A , 116 :21012 , 2019
Abstract : Insecticides allow control of agricultural pests and disease vectors and are vital for global food security and health. The evolution of resistance to insecticides, such as organophosphates (OPs), is a serious and growing concern. OP resistance often involves sequestration or hydrolysis of OPs by carboxylesterases. Inhibiting carboxylesterases could, therefore, restore the effectiveness of OPs for which resistance has evolved. Here, we use covalent virtual screening to produce nano-/picomolar boronic acid inhibitors of the carboxylesterase alphaE7 from the agricultural pest Lucilia cuprina as well as a common Gly137Asp alphaE7 mutant that confers OP resistance. These inhibitors, with high selectivity against human acetylcholinesterase and low to no toxicity in human cells and in mice, act synergistically with the OPs diazinon and malathion to reduce the amount of OP required to kill L. cuprina by up to 16-fold and abolish resistance. The compounds exhibit broad utility in significantly potentiating another OP, chlorpyrifos, against the common pest, the peach-potato aphid (Myzus persicae). These compounds represent a solution to OP resistance as well as to environmental concerns regarding overuse of OPs, allowing significant reduction of use without compromising efficacy.
ESTHER : Correy_2019_Proc.Natl.Acad.Sci.U.S.A_116_21012
PubMedSearch : Correy_2019_Proc.Natl.Acad.Sci.U.S.A_116_21012
PubMedID: 31575743
Gene_locus related to this paper: luccu-E3aest7

Title : Molecular basis for the behavioral effects of the odorant degrading enzyme Esterase 6 in Drosophila - Younus_2017_Sci.Rep_7_46188
Author(s) : Younus F , Fraser NJ , Coppin CW , Liu JW , Correy GJ , Chertemps T , Pandey G , Maibeche M , Jackson CJ , Oakeshott JG
Ref : Sci Rep , 7 :46188 , 2017
Abstract : Previous electrophysiological and behavioural studies implicate esterase 6 in the processing of the pheromone cis-vaccenyl acetate and various food odorants that affect aggregation and reproductive behaviours. Here we show esterase 6 has relatively high activity against many of the short-mid chain food esters, but negligible activity against cis-vaccenyl acetate. The crystal structure of esterase 6 confirms its substrate-binding site can accommodate many short-mid chain food esters but not cis-vaccenyl acetate. Immunohistochemical assays show esterase 6 is expressed in non-neuronal cells in the third antennal segment that could be accessory or epidermal cells surrounding numerous olfactory sensilla, including basiconics involved in food odorant detection. Esterase 6 is also produced in trichoid sensilla, but not in the same cell types as the cis-vaccenyl acetate binding protein LUSH. Our data support a model in which esterase 6 acts as a direct odorant degrading enzyme for many bioactive food esters, but not cis-vaccenyl acetate.
ESTHER : Younus_2017_Sci.Rep_7_46188
PubMedSearch : Younus_2017_Sci.Rep_7_46188
PubMedID: 28393888
Gene_locus related to this paper: drome-este6

Title : Laboratory evolution of protein conformational dynamics - Campbell_2017_Curr.Opin.Struct.Biol_50_49
Author(s) : Campbell EC , Correy GJ , Mabbitt PD , Buckle AM , Tokuriki N , Jackson CJ
Ref : Current Opinion in Structural Biology , 50 :49 , 2017
Abstract : This review focuses on recent work that has begun to establish specific functional roles for protein conformational dynamics, specifically how the conformational landscapes that proteins can sample can evolve under laboratory based evolutionary selection. We discuss recent technical advances in computational and biophysical chemistry, which have provided us with new ways to dissect evolutionary processes. Finally, we offer some perspectives on the emerging view of conformational dynamics and evolution, and the challenges that we face in rationally engineering conformational dynamics.
ESTHER : Campbell_2017_Curr.Opin.Struct.Biol_50_49
PubMedSearch : Campbell_2017_Curr.Opin.Struct.Biol_50_49
PubMedID: 29120734

Title : Evolution of Protein Quaternary Structure in Response to Selective Pressure for Increased Thermostability - Fraser_2016_J.Mol.Biol_428_2359
Author(s) : Fraser NJ , Liu JW , Mabbitt PD , Correy GJ , Coppin CW , Lethier M , Perugini MA , Murphy JM , Oakeshott JG , Weik M , Jackson CJ
Ref : Journal of Molecular Biology , 428 :2359 , 2016
Abstract : Oligomerization has been suggested to be an important mechanism for increasing or maintaining the thermostability of proteins. Although it is evident that protein-protein contacts can result in substantial stabilization in many extant proteins, evidence for evolutionary selection for oligomerization is largely indirect and little is understood of the early steps in the evolution of oligomers. A laboratory-directed evolution experiment that selected for increased thermostability in the alphaE7 carboxylesterase from the Australian sheep blowfly, Lucilia cuprina, resulted in a thermostable variant, LcalphaE7-4a, that displayed increased levels of dimeric and tetrameric quaternary structure. A trade-off between activity and thermostability was made during the evolution of thermostability, with the higher-order oligomeric species displaying the greatest thermostability and lowest catalytic activity. Analysis of monomeric and dimeric LcalphaE7-4a crystal structures revealed that only one of the oligomerization-inducing mutations was located at a potential protein-protein interface. This work demonstrates that by imposing a selective pressure demanding greater thermostability, mutations can lead to increased oligomerization and stabilization, providing support for the hypothesis that oligomerization is a viable evolutionary strategy for protein stabilization.
ESTHER : Fraser_2016_J.Mol.Biol_428_2359
PubMedSearch : Fraser_2016_J.Mol.Biol_428_2359
PubMedID: 27016206
Gene_locus related to this paper: luccu-E3aest7

Title : The role of protein dynamics in the evolution of new enzyme function - Campbell_2016_Nat.Chem.Biol_12_944
Author(s) : Campbell EC , Kaltenbach M , Correy GJ , Carr PD , Porebski BT , Livingstone EK , Afriat-Jurnou L , Buckle AM , Weik M , Hollfelder F , Tokuriki N , Jackson CJ
Ref : Nat Chemical Biology , 12 :944 , 2016
Abstract : Enzymes must be ordered to allow the stabilization of transition states by their active sites, yet dynamic enough to adopt alternative conformations suited to other steps in their catalytic cycles. The biophysical principles that determine how specific protein dynamics evolve and how remote mutations affect catalytic activity are poorly understood. Here we examine a 'molecular fossil record' that was recently obtained during the laboratory evolution of a phosphotriesterase from Pseudomonas diminuta to an arylesterase. Analysis of the structures and dynamics of nine protein variants along this trajectory, and three rationally designed variants, reveals cycles of structural destabilization and repair, evolutionary pressure to 'freeze out' unproductive motions and sampling of distinct conformations with specific catalytic properties in bi-functional intermediates. This work establishes that changes to the conformational landscapes of proteins are an essential aspect of molecular evolution and that change in function can be achieved through enrichment of preexisting conformational sub-states.
ESTHER : Campbell_2016_Nat.Chem.Biol_12_944
PubMedSearch : Campbell_2016_Nat.Chem.Biol_12_944
PubMedID: 27618189

Title : Mapping the Accessible Conformational Landscape of an Insect Carboxylesterase Using Conformational Ensemble Analysis and Kinetic Crystallography - Correy_2016_Structure_24_977
Author(s) : Correy GJ , Carr PD , Meirelles T , Mabbitt PD , Fraser NJ , Weik M , Jackson CJ
Ref : Structure , 24 :977 , 2016
Abstract : The proper function of enzymes often depends upon their efficient interconversion between particular conformational sub-states on a free-energy landscape. Experimentally characterizing these sub-states is challenging, which has limited our understanding of the role of protein dynamics in many enzymes. Here, we have used a combination of kinetic crystallography and detailed analysis of crystallographic protein ensembles to map the accessible conformational landscape of an insect carboxylesterase (LcalphaE7) as it traverses all steps in its catalytic cycle. LcalphaE7 is of special interest because of its evolving role in organophosphate insecticide resistance. Our results reveal that a dynamically coupled network of residues extends from the substrate-binding site to a surface loop. Interestingly, the coupling of this network that is apparent in the apoenzyme appears to be reduced in the phosphorylated enzyme intermediate. Altogether, the results of this work highlight the importance of protein dynamics to enzyme function and the evolution of new activity.
ESTHER : Correy_2016_Structure_24_977
PubMedSearch : Correy_2016_Structure_24_977
PubMedID: 27210287
Gene_locus related to this paper: luccu-E3aest7

Title : Conformational Disorganization within the Active Site of a Recently Evolved Organophosphate Hydrolase Limits Its Catalytic Efficiency - Mabbitt_2016_Biochemistry_55_1408
Author(s) : Mabbitt PD , Correy GJ , Meirelles T , Fraser NJ , Coote ML , Jackson CJ
Ref : Biochemistry , 55 :1408 , 2016
Abstract : The evolution of new enzymatic activity is rarely observed outside of the laboratory. In the agricultural pest Lucilia cuprina, a naturally occurring mutation (Gly137Asp) in alpha-esterase 7 (LcalphaE7) results in acquisition of organophosphate hydrolase activity and confers resistance to organophosphate insecticides. Here, we present an X-ray crystal structure of LcalphaE7:Gly137Asp that, along with kinetic data, suggests that Asp137 acts as a general base in the new catalytic mechanism. Unexpectedly, the conformation of Asp137 observed in the crystal structure obstructs the active site and is not catalytically productive. Molecular dynamics simulations reveal that alternative, catalytically competent conformers of Asp137 are sampled on the nanosecond time scale, although these states are less populated. Thus, although the mutation introduces the new reactive group responsible for organophosphate detoxification, the catalytic efficiency appears to be limited by conformational disorganization: the frequent sampling of low-energy nonproductive states. This result is consistent with a model of molecular evolution in which initial function-changing mutations can result in enzymes that display only a fraction of their catalytic potential due to conformational disorganization.
ESTHER : Mabbitt_2016_Biochemistry_55_1408
PubMedSearch : Mabbitt_2016_Biochemistry_55_1408
PubMedID: 26881849
Gene_locus related to this paper: luccu-E3aest7