6yvs: Difference between revisions
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==FOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH 5-{4-[(Pyridin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one== | |||
<StructureSection load='6yvs' size='340' side='right'caption='[[6yvs]], [[Resolution|resolution]] 1.81Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YVS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YVS FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.81Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PVT:5-[[4-(pyridin-3-ylmethylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-1,3-dihydroindol-2-one'>PVT</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6yvs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yvs OCA], [https://pdbe.org/6yvs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yvs RCSB], [https://www.ebi.ac.uk/pdbsum/6yvs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yvs ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
There 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<ref>PMID:33497606</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Amaral | <div class="pdbe-citations 6yvs" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: | ==See Also== | ||
*[[Focal adhesion kinase 3D structures|Focal adhesion kinase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Amaral M]] | |||
[[Category: Heinrich T]] | |||
[[Category: Musil D]] | |||
Latest revision as of 05:59, 21 November 2024
FOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH 5-{4-[(Pyridin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one
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