7vko

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==Crystal structure of TrkA kinase with repotrectinib==
==Crystal structure of TrkA kinase with repotrectinib==
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<StructureSection load='7vko' size='340' side='right'caption='[[7vko]]' scene=''>
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<StructureSection load='7vko' size='340' side='right'caption='[[7vko]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7VKO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7VKO FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7vko]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7VKO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7VKO FirstGlance]. <br>
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</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=7vko FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7vko OCA], [https://pdbe.org/7vko PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7vko RCSB], [https://www.ebi.ac.uk/pdbsum/7vko PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7vko ProSAT]</span></td></tr>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7GI:Repotrectinib'>7GI</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7vko FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7vko OCA], [https://pdbe.org/7vko PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7vko RCSB], [https://www.ebi.ac.uk/pdbsum/7vko PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7vko ProSAT]</span></td></tr>
</table>
</table>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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NTRK chromosomal rearrangements yield oncogenic TRK fusion proteins that are sensitive to TRK inhibitors (larotrectinib and entrectinib) but often mutate, limiting the durability of response for NTRK (+) patients. Next-generation inhibitors with compact macrocyclic structures (repotrectinib and selitrectinib) were designed to avoid resistance mutations. Head-to-head potency comparisons of TRK inhibitors and molecular characterization of binding interactions are incomplete, obscuring a detailed understanding of how molecular characteristics translate to potency. Larotrectinib, entrectinib, selitrectinib, and repotrectinib were characterized using cellular models of wild-type TRKA/B/C fusions and resistance mutant variants with a subset evaluated in xenograft tumor models. Crystal structures were determined for repotrectinib bound to TRKA (wild-type, solvent-front mutant). TKI-naive and pretreated case studies are presented. Repotrectinib was the most potent inhibitor of wild-type TRKA/B/C fusions and was more potent than selitrectinib against all tested resistance mutations, underscoring the importance of distinct features of the macrocycle structures. Cocrystal structures of repotrectinib with wild-type TRKA and the TRKA(G595R) SFM variant elucidated how differences in macrocyclic inhibitor structure, binding orientation, and conformational flexibility affect potency and mutant selectivity. The SFM crystal structure revealed an unexpected intramolecular arginine sidechain interaction. Repotrectinib caused tumor regression in LMNA-NTRK1 xenograft models harboring GKM, SFM, xDFG, and GKM + SFM compound mutations. Durable responses were observed in TKI-naive and -pretreated patients with NTRK (+) cancers treated with repotrectinib (NCT03093116). This comprehensive analysis of first- and second-generation TRK inhibitors informs the clinical utility, structural determinants of inhibitor potency, and design of new generations of macrocyclic inhibitors.
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Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations.,Murray BW, Rogers E, Zhai D, Deng W, Chen X, Sprengeler PA, Zhang X, Graber A, Reich SH, Stopatschinskaja S, Solomon B, Besse B, Drilon A Mol Cancer Ther. 2021 Dec;20(12):2446-2456. doi: 10.1158/1535-7163.MCT-21-0632., Epub 2021 Oct 8. PMID:34625502<ref>PMID:34625502</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7vko" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Besse B]]
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[[Category: Receptor protein-tyrosine kinase]]
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[[Category: Chen X]]
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[[Category: Besse, B]]
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[[Category: Deng W]]
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[[Category: Chen, X]]
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[[Category: Drilon A]]
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[[Category: Deng, W]]
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[[Category: Graber A]]
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[[Category: Drilon, A]]
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[[Category: Murray BW]]
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[[Category: Graber, A]]
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[[Category: Reich SH]]
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[[Category: Murray, B W]]
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[[Category: Rogers E]]
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[[Category: Reich, S H]]
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[[Category: Solomon B]]
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[[Category: Rogers, E]]
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[[Category: Sprengeler PA]]
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[[Category: Solomon, B]]
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[[Category: Stopatschinskaja S]]
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[[Category: Sprengeler, P A]]
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[[Category: Zhai D]]
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[[Category: Stopatschinskaja, S]]
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[[Category: Zhang X]]
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[[Category: Zhai, D]]
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[[Category: Zhang, X]]
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[[Category: Drug resistance]]
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[[Category: Macrocyclic inhibitor]]
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[[Category: Ntrk]]
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[[Category: Repotrectinib]]
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[[Category: Transferase]]
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[[Category: Trk]]

Revision as of 08:47, 23 February 2022

Crystal structure of TrkA kinase with repotrectinib

PDB ID 7vko

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