6yxv
From Proteopedia
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==FOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH N-Methyl-N-{3-[(2-phenylamino-5-trifluoromethyl-pyrimidin-4-ylamino)-methyl]-pyridin-2-yl}-methanesulfonamide== | ==FOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH N-Methyl-N-{3-[(2-phenylamino-5-trifluoromethyl-pyrimidin-4-ylamino)-methyl]-pyridin-2-yl}-methanesulfonamide== | ||
| - | <StructureSection load='6yxv' size='340' side='right'caption='[[6yxv]]' scene=''> | + | <StructureSection load='6yxv' size='340' side='right'caption='[[6yxv]], [[Resolution|resolution]] 2.30Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YXV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YXV FirstGlance]. <br> | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YXV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YXV FirstGlance]. <br> | ||
| - | </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=6yxv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yxv OCA], [https://pdbe.org/6yxv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yxv RCSB], [https://www.ebi.ac.uk/pdbsum/6yxv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yxv ProSAT]</span></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.298Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=Q2H:~{N}-methyl-~{N}-[3-[(~{E})-[2-phenylazanyl-5-(trifluoromethyl)pyrimidin-4-yl]iminomethyl]pyridin-2-yl]methanesulfonamide'>Q2H</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=6yxv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yxv OCA], [https://pdbe.org/6yxv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yxv RCSB], [https://www.ebi.ac.uk/pdbsum/6yxv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yxv ProSAT]</span></td></tr> | ||
</table> | </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> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6yxv" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Focal adhesion kinase 3D structures|Focal adhesion kinase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Current revision
FOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH N-Methyl-N-{3-[(2-phenylamino-5-trifluoromethyl-pyrimidin-4-ylamino)-methyl]-pyridin-2-yl}-methanesulfonamide
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