4x1k: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4x1k]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Ovis_aries Ovis aries] and [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4X1K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4X1K FirstGlance]. <br> | <table><tr><td colspan='2'>[[4x1k]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Ovis_aries Ovis aries] and [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4X1K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4X1K FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3WZ:2-METHYL-L-ALANYL-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S)-1-CARBOXY-2-PHENYLETHYL]AMINO}-1-METHOXY-2-METHYL-3-OXOPROPYL]PYRROLIDIN-1-YL}-3-METHOXY-5-METHYL-1-OXOHEPTAN-4-YL]-N-METHYL-L-VALINAMIDE'>3WZ</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=GTP:GUANOSINE-5-TRIPHOSPHATE'>GTP</scene>, <scene name='pdbligand=LOC:N-[(7S)-1,2,3,10-TETRAMETHOXY-9-OXO-6,7-DIHYDRO-5H-BENZO[D]HEPTALEN-7-YL]ETHANAMIDE'>LOC</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></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]] 3.5Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3WZ:2-METHYL-L-ALANYL-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S)-1-CARBOXY-2-PHENYLETHYL]AMINO}-1-METHOXY-2-METHYL-3-OXOPROPYL]PYRROLIDIN-1-YL}-3-METHOXY-5-METHYL-1-OXOHEPTAN-4-YL]-N-METHYL-L-VALINAMIDE'>3WZ</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=GTP:GUANOSINE-5-TRIPHOSPHATE'>GTP</scene>, <scene name='pdbligand=LOC:N-[(7S)-1,2,3,10-TETRAMETHOXY-9-OXO-6,7-DIHYDRO-5H-BENZO[D]HEPTALEN-7-YL]ETHANAMIDE'>LOC</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=4x1k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x1k OCA], [https://pdbe.org/4x1k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4x1k RCSB], [https://www.ebi.ac.uk/pdbsum/4x1k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4x1k ProSAT]</span></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=4x1k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x1k OCA], [https://pdbe.org/4x1k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4x1k RCSB], [https://www.ebi.ac.uk/pdbsum/4x1k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4x1k ProSAT]</span></td></tr> | ||
</table> | </table> | ||
Latest revision as of 10:39, 27 September 2023
Discovery of cytotoxic Dolastatin 10 analogs with N-terminal modificationsDiscovery of cytotoxic Dolastatin 10 analogs with N-terminal modifications
Structural highlights
FunctionSTMN4_RAT Exhibits microtubule-destabilizing activity.[1] [2] [3] Publication Abstract from PubMedAuristatins, synthetic analogues of the antineoplastic natural product Dolastatin 10, are ultrapotent cytotoxic microtubule inhibitors that are clinically used as payloads in antibody-drug conjugates (ADCs). The design and synthesis of several new auristatin analogues with N-terminal modifications that include amino acids with alpha,alpha-disubstituted carbon atoms are described, including the discovery of our lead auristatin, PF-06380101. This modification of the peptide structure is unprecedented and led to analogues with excellent potencies in tumor cell proliferation assays and differential ADME properties when compared to other synthetic auristatin analogues that are used in the preparation of ADCs. In addition, auristatin cocrystal structures with tubulin are being presented that allow for the detailed examination of their binding modes. A surprising finding is that all analyzed analogues have a cis-configuration at the Val-Dil amide bond in their functionally relevant tubulin bound state, whereas in solution this bond is exclusively in the trans-configuration. This remarkable observation shines light onto the preferred binding mode of auristatins and serves as a valuable tool for structure-based drug design. Discovery of cytotoxic dolastatin 10 analogues with N-terminal modifications.,Maderna A, Doroski M, Subramanyam C, Porte A, Leverett CA, Vetelino BC, Chen Z, Risley H, Parris K, Pandit J, Varghese AH, Shanker S, Song C, Sukuru SC, Farley KA, Wagenaar MM, Shapiro MJ, Musto S, Lam MH, Loganzo F, O'Donnell CJ J Med Chem. 2014 Dec 26;57(24):10527-43. doi: 10.1021/jm501649k. Epub 2014 Dec 9. PMID:25431858[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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