Structural highlights
Publication Abstract from PubMedThere is increasing evidence of a significant correlation between prolonged drug-target residence time and increased drug efficacy. Here, we report a structural rationale for kinetic selectivity between two closely related kinases: focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2). We found that slowly dissociating FAK inhibitors induce helical structure at the DFG motif of FAK but not PYK2. Binding kinetic data, high-resolution structures and mutagenesis data support the role of hydrophobic interactions of inhibitors with the DFG-helical region, providing a structural rationale for slow dissociation rates from FAK and kinetic selectivity over PYK2. Our experimental data correlate well with computed relative residence times from molecular simulations, supporting a feasible strategy for rationally optimizing ligand residence times. We suggest that the interplay between the protein structural mobility and ligand-induced effects is a key regulator of the kinetic selectivity of inhibitors of FAK versus PYK2. Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2.,Berger BT, Amaral M, Kokh DB, Nunes-Alves A, Musil D, Heinrich T, Schroder M, Neil R, Wang J, Navratilova I, Bomke J, Elkins JM, Muller S, Frech M, Wade RC, Knapp S Cell Chem Biol. 2021 Jan 21. pii: S2451-9456(21)00003-9. doi:, 10.1016/j.chembiol.2021.01.003. PMID:33497606[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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