Kruse AC

References (7)

Title : Muscarinic acetylcholine receptor X-ray structures: potential implications for drug development - Kruse_2014_Curr.Opin.Pharmacol_16_24
Author(s) : Kruse AC , Hu J , Kobilka BK , Wess J
Ref : Curr Opin Pharmacol , 16 :24 , 2014
Abstract : Muscarinic acetylcholine receptor antagonists are widely used as bronchodilating drugs in pulmonary medicine. The therapeutic efficacy of these agents depends on the blockade of M3 muscarinic receptors expressed on airway smooth muscle cells. All muscarinic antagonists currently used as bronchodilating agents show high affinity for all five muscarinic receptor subtypes, thus increasing the likelihood of unwanted side effects. Recent X-ray crystallographic studies have provided detailed structural information about the nature of the orthosteric muscarinic binding site (the conventional acetylcholine binding site) and an 'outer' receptor cavity that can bind allosteric (non-orthosteric) drugs. These new findings should guide the development of selective M3 receptor blockers that have little or no effect on other muscarinic receptor subtypes.
ESTHER : Kruse_2014_Curr.Opin.Pharmacol_16_24
PubMedSearch : Kruse_2014_Curr.Opin.Pharmacol_16_24
PubMedID: 24662799

Title : Muscarinic acetylcholine receptors: novel opportunities for drug development - Kruse_2014_Nat.Rev.Drug.Discov_13_549
Author(s) : Kruse AC , Kobilka BK , Gautam D , Sexton PM , Christopoulos A , Wess J
Ref : Nat Rev Drug Discov , 13 :549 , 2014
Abstract : The muscarinic acetylcholine receptors are a subfamily of G protein-coupled receptors that regulate numerous fundamental functions of the central and peripheral nervous system. The past few years have witnessed unprecedented new insights into muscarinic receptor physiology, pharmacology and structure. These advances include the first structural views of muscarinic receptors in both inactive and active conformations, as well as a better understanding of the molecular underpinnings of muscarinic receptor regulation by allosteric modulators. These recent findings should facilitate the development of new muscarinic receptor subtype-selective ligands that could prove to be useful for the treatment of many severe pathophysiological conditions.
ESTHER : Kruse_2014_Nat.Rev.Drug.Discov_13_549
PubMedSearch : Kruse_2014_Nat.Rev.Drug.Discov_13_549
PubMedID: 24903776

Title : Novel insights into m3 muscarinic acetylcholine receptor physiology and structure - Kruse_2014_J.Mol.Neurosci_53_316
Author(s) : Kruse AC , Li J , Hu J , Kobilka BK , Wess J
Ref : Journal of Molecular Neuroscience , 53 :316 , 2014
Abstract : Recent studies with M3 muscarinic acetylcholine receptor (M3R) mutant mice suggest that drugs selectively targeting this receptor subtype may prove useful for the treatment of various pathophysiological conditions. Moreover, the use of M3R-based designer G protein-coupled receptors (GPCRs) has provided novel insights into how Gq-coupled GPCRs can modulate whole-body glucose homeostasis by acting on specific peripheral cell types. More recently, we succeeded in using X-ray crystallography to determine the structure of the M3R bound to the bronchodilating drug tiotropium, a muscarinic antagonist (inverse agonist). This new structural information should facilitate the development of orthosteric or allosteric M3R-selective drugs that are predicted to have considerable therapeutic potential.
ESTHER : Kruse_2014_J.Mol.Neurosci_53_316
PubMedSearch : Kruse_2014_J.Mol.Neurosci_53_316
PubMedID: 24068573

Title : Activation and allosteric modulation of a muscarinic acetylcholine receptor - Kruse_2013_Nature_504_101
Author(s) : Kruse AC , Ring AM , Manglik A , Hu J , Hu K , Eitel K , Hubner H , Pardon E , Valant C , Sexton PM , Christopoulos A , Felder CC , Gmeiner P , Steyaert J , Weis WI , Garcia KC , Wess J , Kobilka BK
Ref : Nature , 504 :101 , 2013
Abstract : Despite recent advances in crystallography and the availability of G-protein-coupled receptor (GPCR) structures, little is known about the mechanism of their activation process, as only the beta2 adrenergic receptor (beta2AR) and rhodopsin have been crystallized in fully active conformations. Here we report the structure of an agonist-bound, active state of the human M2 muscarinic acetylcholine receptor stabilized by a G-protein mimetic camelid antibody fragment isolated by conformational selection using yeast surface display. In addition to the expected changes in the intracellular surface, the structure reveals larger conformational changes in the extracellular region and orthosteric binding site than observed in the active states of the beta2AR and rhodopsin. We also report the structure of the M2 receptor simultaneously bound to the orthosteric agonist iperoxo and the positive allosteric modulator LY2119620. This structure reveals that LY2119620 recognizes a largely pre-formed binding site in the extracellular vestibule of the iperoxo-bound receptor, inducing a slight contraction of this outer binding pocket. These structures offer important insights into the activation mechanism and allosteric modulation of muscarinic receptors.
ESTHER : Kruse_2013_Nature_504_101
PubMedSearch : Kruse_2013_Nature_504_101
PubMedID: 24256733

Title : Muscarinic receptors as model targets and antitargets for structure-based ligand discovery - Kruse_2013_Mol.Pharmacol_84_528
Author(s) : Kruse AC , Weiss DR , Rossi M , Hu J , Hu K , Eitel K , Gmeiner P , Wess J , Kobilka BK , Shoichet BK
Ref : Molecular Pharmacology , 84 :528 , 2013
Abstract : G protein-coupled receptors (GPCRs) regulate virtually all aspects of human physiology and represent an important class of therapeutic drug targets. Many GPCR-targeted drugs resemble endogenous agonists, often resulting in poor selectivity among receptor subtypes and restricted pharmacologic profiles. The muscarinic acetylcholine receptor family exemplifies these problems; thousands of ligands are known, but few are receptor subtype-selective and nearly all are cationic in nature. Using structure-based docking against the M2 and M3 muscarinic receptors, we screened 3.1 million molecules for ligands with new physical properties, chemotypes, and receptor subtype selectivities. Of 19 docking-prioritized molecules tested against the M2 subtype, 11 had substantial activity and 8 represented new chemotypes. Intriguingly, two were uncharged ligands with low micromolar to high nanomolar Ki values, an observation with few precedents among aminergic GPCRs. To exploit a single amino-acid substitution among the binding pockets between the M2 and M3 receptors, we selected molecules predicted by docking to bind to the M3 and but not the M2 receptor. Of 16 molecules tested, 8 bound to the M3 receptor. Whereas selectivity remained modest for most of these, one was a partial agonist at the M3 receptor without measurable M2 agonism. Consistent with this activity, this compound stimulated insulin release from a mouse beta-cell line. These results support the ability of structure-based discovery to identify new ligands with unexplored chemotypes and physical properties, leading to new biologic functions, even in an area as heavily explored as muscarinic pharmacology.
ESTHER : Kruse_2013_Mol.Pharmacol_84_528
PubMedSearch : Kruse_2013_Mol.Pharmacol_84_528
PubMedID: 23887926

Title : Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist - Haga_2012_Nature_482_547
Author(s) : Haga K , Kruse AC , Asada H , Yurugi-Kobayashi T , Shiroishi M , Zhang C , Weis WI , Okada T , Kobilka BK , Haga T , Kobayashi T
Ref : Nature , 482 :547 , 2012
Abstract : The parasympathetic branch of the autonomic nervous system regulates the activity of multiple organ systems. Muscarinic receptors are G-protein-coupled receptors that mediate the response to acetylcholine released from parasympathetic nerves. Their role in the unconscious regulation of organ and central nervous system function makes them potential therapeutic targets for a broad spectrum of diseases. The M2 muscarinic acetylcholine receptor (M2 receptor) is essential for the physiological control of cardiovascular function through activation of G-protein-coupled inwardly rectifying potassium channels, and is of particular interest because of its extensive pharmacological characterization with both orthosteric and allosteric ligands. Here we report the structure of the antagonist-bound human M2 receptor, the first human acetylcholine receptor to be characterized structurally, to our knowledge. The antagonist 3-quinuclidinyl-benzilate binds in the middle of a long aqueous channel extending approximately two-thirds through the membrane. The orthosteric binding pocket is formed by amino acids that are identical in all five muscarinic receptor subtypes, and shares structural homology with other functionally unrelated acetylcholine binding proteins from different species. A layer of tyrosine residues forms an aromatic cap restricting dissociation of the bound ligand. A binding site for allosteric ligands has been mapped to residues at the entrance to the binding pocket near this aromatic cap. The structure of the M2 receptor provides insights into the challenges of developing subtype-selective ligands for muscarinic receptors and their propensity for allosteric regulation.
ESTHER : Haga_2012_Nature_482_547
PubMedSearch : Haga_2012_Nature_482_547
PubMedID: 22278061

Title : Structure and dynamics of the M3 muscarinic acetylcholine receptor - Kruse_2012_Nature_482_552
Author(s) : Kruse AC , Hu J , Pan AC , Arlow DH , Rosenbaum DM , Rosemond E , Green HF , Liu T , Chae PS , Dror RO , Shaw DE , Weis WI , Wess J , Kobilka BK
Ref : Nature , 482 :552 , 2012
Abstract : Acetylcholine, the first neurotransmitter to be identified, exerts many of its physiological actions via activation of a family of G-protein-coupled receptors (GPCRs) known as muscarinic acetylcholine receptors (mAChRs). Although the five mAChR subtypes (M1-M5) share a high degree of sequence homology, they show pronounced differences in G-protein coupling preference and the physiological responses they mediate. Unfortunately, despite decades of effort, no therapeutic agents endowed with clear mAChR subtype selectivity have been developed to exploit these differences. We describe here the structure of the G(q/11)-coupled M3 mAChR ('M3 receptor', from rat) bound to the bronchodilator drug tiotropium and identify the binding mode for this clinically important drug. This structure, together with that of the G(i/o)-coupled M2 receptor, offers possibilities for the design of mAChR subtype-selective ligands. Importantly, the M3 receptor structure allows a structural comparison between two members of a mammalian GPCR subfamily displaying different G-protein coupling selectivities. Furthermore, molecular dynamics simulations suggest that tiotropium binds transiently to an allosteric site en route to the binding pocket of both receptors. These simulations offer a structural view of an allosteric binding mode for an orthosteric GPCR ligand and provide additional opportunities for the design of ligands with different affinities or binding kinetics for different mAChR subtypes. Our findings not only offer insights into the structure and function of one of the most important GPCR families, but may also facilitate the design of improved therapeutics targeting these critical receptors.
ESTHER : Kruse_2012_Nature_482_552
PubMedSearch : Kruse_2012_Nature_482_552
PubMedID: 22358844