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- W2033611080 startingPage "246" @default.
- W2033611080 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." @default.
- W2033611080 created "2016-06-24" @default.
- W2033611080 creator A5037144273 @default.
- W2033611080 creator A5051355630 @default.
- W2033611080 date "2014-07-14" @default.
- W2033611080 modified "2023-10-16" @default.
- W2033611080 title "Molecular Basis for Small Molecule Inhibition of G Protein-Coupled Receptor Kinases" @default.
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- W2033611080 doi "https://doi.org/10.1021/cb5003976" @default.
- W2033611080 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4301174" @default.
- W2033611080 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/24984143" @default.
- W2033611080 hasPublicationYear "2014" @default.
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