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| | ==Discovery of cytotoxic Dolastatin 10 analogs with N-terminal modifications== | | ==Discovery of cytotoxic Dolastatin 10 analogs with N-terminal modifications== |
| - | <StructureSection load='4x1i' size='340' side='right' caption='[[4x1i]], [[Resolution|resolution]] 3.11Å' scene=''> | + | <StructureSection load='4x1i' size='340' side='right'caption='[[4x1i]], [[Resolution|resolution]] 3.11Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4x1i]] is a 5 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat] and [http://en.wikipedia.org/wiki/Ovis_aries Ovis aries]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4X1I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4X1I FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4x1i]] 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=4X1I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4X1I FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3WD:2-methyl-L-alanyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide'>3WD</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3WD:2-methyl-L-alanyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide'>3WD</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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4x1k|4x1k]], [[4x1y|4x1y]], [[4x20|4x20]]</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=4x1i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x1i OCA], [https://pdbe.org/4x1i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4x1i RCSB], [https://www.ebi.ac.uk/pdbsum/4x1i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4x1i ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Stmn4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4x1i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x1i OCA], [http://pdbe.org/4x1i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4x1i RCSB], [http://www.ebi.ac.uk/pdbsum/4x1i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4x1i ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/D0VWZ0_SHEEP D0VWZ0_SHEEP]] Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain (By similarity).[RuleBase:RU003505][SAAS:SAAS023123_004_019801] [[http://www.uniprot.org/uniprot/STMN4_RAT STMN4_RAT]] Exhibits microtubule-destabilizing activity.<ref>PMID:15039434</ref> <ref>PMID:12111843</ref> <ref>PMID:15014504</ref> [[http://www.uniprot.org/uniprot/D0VWY9_SHEEP D0VWY9_SHEEP]] Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain (By similarity).[RuleBase:RU003505] | + | [https://www.uniprot.org/uniprot/D0VWZ0_SHEEP D0VWZ0_SHEEP] Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain (By similarity).[RuleBase:RU003505][SAAS:SAAS023123_004_019801] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4x1i" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4x1i" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Stathmin-4 3D structures|Stathmin-4 3D structures]] |
| | + | *[[Tubulin 3D Structures|Tubulin 3D Structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Buffalo rat]] | + | [[Category: Large Structures]] |
| | [[Category: Ovis aries]] | | [[Category: Ovis aries]] |
| - | [[Category: Parris, K D]] | + | [[Category: Rattus norvegicus]] |
| - | [[Category: Binding site]] | + | [[Category: Parris KD]] |
| - | [[Category: Cattle]]
| + | |
| - | [[Category: Colchicine]]
| + | |
| - | [[Category: Competitive]]
| + | |
| - | [[Category: Human]]
| + | |
| - | [[Category: Microtubule]]
| + | |
| - | [[Category: Protein binding]]
| + | |
| - | [[Category: Protein conformation]]
| + | |
| - | [[Category: Protein multimerization]]
| + | |
| - | [[Category: Structural protein-inhibitor complex]]
| + | |
| - | [[Category: Tubulin]]
| + | |
| - | [[Category: Tubulin modulator]]
| + | |
| - | [[Category: Tumor]]
| + | |
| Structural highlights
Function
D0VWZ0_SHEEP Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain (By similarity).[RuleBase:RU003505][SAAS:SAAS023123_004_019801]
Publication Abstract from PubMed
Auristatins, 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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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. Discovery of cytotoxic dolastatin 10 analogues with N-terminal modifications. J Med Chem. 2014 Dec 26;57(24):10527-43. doi: 10.1021/jm501649k. Epub 2014 Dec 9. PMID:25431858 doi:http://dx.doi.org/10.1021/jm501649k
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