View source for 6yvy


==FOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH 4-{[4-{[(1R,2R)-2-(dimethylamino)cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-N-methylbenzenesulfonamide==
<StructureSection load='6yvy' size='340' side='right'caption='[[6yvy]], [[Resolution|resolution]] 1.92&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YVY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YVY 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]] 1.918&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=P1E:4-{[4-{[(1R,2R)-2-(DIMETHYLAMINO)CYCLOPENTYL]AMINO}-5-(TRIFLUOROMETHYL)PYRIMIDIN-2-YL]AMINO}-N-METHYLBENZENESULFONAMIDE'>P1E</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=6yvy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yvy OCA], [https://pdbe.org/6yvy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yvy RCSB], [https://www.ebi.ac.uk/pdbsum/6yvy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yvy 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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6yvy" style="background-color:#fffaf0;"></div>

==See Also==
*[[Focal adhesion kinase 3D structures|Focal adhesion kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Amaral M]]
[[Category: Musil D]]