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Molecular basis for small molecule inhibition of G protein-coupled receptor kinases.

ABSTRACT: Small molecules that inhibit the protein kinase A, G, and C (AGC) family of serine/threonine kinases can exert profound effects on cell homeostasis and thereby regulate fundamental processes such as heart rate, blood pressure, and metabolism, but there is not yet a clinically approved drug in the United States selective for a member of this family. One subfamily of AGC kinases, the G protein-coupled receptor (GPCR) kinases (GRKs), initiates the desensitization of active GPCRs. Of these, GRK2 has been directly implicated in the progression of heart failure. Thus, there is great interest in the identification of GRK2-specific chemical probes that can be further developed into therapeutics. Herein, we compare crystal structures of small molecule inhibitors in complex with GRK2 to those of highly selective compounds in complex with Rho-associated coiled-coil containing kinase 1 (ROCK1), a closely related AGC kinase. This analysis suggests that reduced hydrogen-bond formation with the hinge of the kinase domain, occupation of the hydrophobic subsite, and, consequently, higher buried surface area are key drivers of potency and selectivity among GRK inhibitors.

SUBMITTER: Homan KT

PROVIDER: S-EPMC4301174 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Molecular basis for small molecule inhibition of G protein-coupled receptor kinases.

Homan Kristoff T KT Tesmer John J G JJ

ACS chemical biology 20140714 1

Small molecules that inhibit the protein kinase A, G, and C (AGC) family of serine/threonine kinases can exert profound effects on cell homeostasis and thereby regulate fundamental processes such as heart rate, blood pressure, and metabolism, but there is not yet a clinically approved drug in the United States selective for a member of this family. One subfamily of AGC kinases, the G protein-coupled receptor (GPCR) kinases (GRKs), initiates the desensitization of active GPCRs. Of these, GRK2 has ...[more]

PMID: 24984143

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Project description:Adhesion G protein-coupled receptors (aGPCRs) have emerging roles in development and tissue maintenance and is the most prevalent GPCR subclass mutated in human cancers, but to date, no drugs have been developed to target them in any disease. aGPCR extracellular domains contain a conserved subdomain that mediates self-cleavage proximal to the start of the 7-transmembrane domain (7TM). The two receptor protomers, extracellular domain and amino terminal fragment (NTF), and the 7TM or C-terminal fragment remain noncovalently bound at the plasma membrane in a low-activity state. We recently demonstrated that NTF dissociation liberates the 7TM N-terminal stalk, which acts as a tethered-peptide agonist permitting receptor-dependent heterotrimeric G protein activation. In many cases, natural aGPCR ligands are extracellular matrix proteins that dissociate the NTF to reveal the tethered agonist. Given the perceived difficulty in modifying extracellular matrix proteins to create aGPCR probes, we developed a serum response element (SRE)-luciferase-based screening approach to identify GPR56/ADGRG1 small-molecule inhibitors. A 2000-compound library comprising known drugs and natural products was screened for GPR56-dependent SRE activation inhibitors that did not inhibit constitutively active G?13-dependent SRE activation. Dihydromunduletone (DHM), a rotenoid derivative, was validated using cell-free aGPCR/heterotrimeric G protein guanosine 5'-3-O-(thio)triphosphate binding reconstitution assays. DHM inhibited GPR56 and GPR114/ADGRG5, which have similar tethered agonists, but not the aGPCR GPR110/ADGRF1, M3 muscarinic acetylcholine, or ?2 adrenergic GPCRs. DHM inhibited tethered peptide agonist-stimulated and synthetic peptide agonist-stimulated GPR56 but did not inhibit basal activity, demonstrating that it antagonizes the peptide agonist. DHM is a novel aGPCR antagonist and potentially useful chemical probe that may be developed as a future aGPCR therapeutic.

Dataset Information

Molecular basis for small molecule inhibition of G protein-coupled receptor kinases.

Publications

Molecular basis for small molecule inhibition of G protein-coupled receptor kinases.

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