6p11: Difference between revisions
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New page: '''Unreleased structure''' The entry 6p11 is ON HOLD Authors: Pisa, R., Cupido, T., Kapoor, T.M. Description: Structure of spastin AAA domain T692A mutant in complex with JNJ-7706621 i... |
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==Structure of spastin AAA domain (T692A mutant) in complex with JNJ-7706621 inhibitor== | |||
<StructureSection load='6p11' size='340' side='right'caption='[[6p11]], [[Resolution|resolution]] 2.15Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6p11]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Drosophila_melanogaster Drosophila melanogaster]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6P11 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6P11 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]] 2.15Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=SKE:4-({5-AMINO-1-[(2,6-DIFLUOROPHENYL)CARBONYL]-1H-1,2,4-TRIAZOL-3-YL}AMINO)BENZENESULFONAMIDE'>SKE</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=6p11 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p11 OCA], [https://pdbe.org/6p11 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6p11 RCSB], [https://www.ebi.ac.uk/pdbsum/6p11 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6p11 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/SPAST_DROME SPAST_DROME] ATP-dependent microtubule severing protein. Stimulates microtubule minus-end depolymerization and poleward microtubule flux in the mitotic spindle. Regulates microtubule stability in the neuromuscular junction synapse.<ref>PMID:15242610</ref> <ref>PMID:15562320</ref> <ref>PMID:15823537</ref> <ref>PMID:16276413</ref> <ref>PMID:17452528</ref> <ref>PMID:19341724</ref> <ref>PMID:18202664</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Drug-like inhibitors are often designed by mimicking cofactor or substrate interactions with enzymes. However, as active sites are comprised of conserved residues, it is difficult to identify the critical interactions needed to design selective inhibitors. We are developing an approach, named RADD (resistance analysis during design), which involves engineering point mutations in the target to generate active alleles and testing compounds against them. Mutations that alter compound potency identify residues that make key interactions with the inhibitor and predict target-binding poses. Here, we apply this approach to analyze how diaminotriazole-based inhibitors bind spastin, a microtubule-severing AAA (ATPase associated with diverse cellular activities) protein. The distinct binding poses predicted for two similar inhibitors were confirmed by a series of X-ray structures. Importantly, our approach not only reveals how selective inhibition of the target can be achieved but also identifies resistance-conferring mutations at the early stages of the design process. | |||
Analyzing Resistance to Design Selective Chemical Inhibitors for AAA Proteins.,Pisa R, Cupido T, Steinman JB, Jones NH, Kapoor TM Cell Chem Biol. 2019 Jun 26. pii: S2451-9456(19)30182-5. doi:, 10.1016/j.chembiol.2019.06.001. PMID:31257183<ref>PMID:31257183</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6p11" style="background-color:#fffaf0;"></div> | ||
[[Category: Cupido | == References == | ||
[[Category: Kapoor | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Drosophila melanogaster]] | |||
[[Category: Large Structures]] | |||
[[Category: Cupido T]] | |||
[[Category: Kapoor TM]] | |||
[[Category: Pisa R]] | |||
Latest revision as of 10:21, 11 October 2023
Structure of spastin AAA domain (T692A mutant) in complex with JNJ-7706621 inhibitorStructure of spastin AAA domain (T692A mutant) in complex with JNJ-7706621 inhibitor
Structural highlights
FunctionSPAST_DROME ATP-dependent microtubule severing protein. Stimulates microtubule minus-end depolymerization and poleward microtubule flux in the mitotic spindle. Regulates microtubule stability in the neuromuscular junction synapse.[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedDrug-like inhibitors are often designed by mimicking cofactor or substrate interactions with enzymes. However, as active sites are comprised of conserved residues, it is difficult to identify the critical interactions needed to design selective inhibitors. We are developing an approach, named RADD (resistance analysis during design), which involves engineering point mutations in the target to generate active alleles and testing compounds against them. Mutations that alter compound potency identify residues that make key interactions with the inhibitor and predict target-binding poses. Here, we apply this approach to analyze how diaminotriazole-based inhibitors bind spastin, a microtubule-severing AAA (ATPase associated with diverse cellular activities) protein. The distinct binding poses predicted for two similar inhibitors were confirmed by a series of X-ray structures. Importantly, our approach not only reveals how selective inhibition of the target can be achieved but also identifies resistance-conferring mutations at the early stages of the design process. Analyzing Resistance to Design Selective Chemical Inhibitors for AAA Proteins.,Pisa R, Cupido T, Steinman JB, Jones NH, Kapoor TM Cell Chem Biol. 2019 Jun 26. pii: S2451-9456(19)30182-5. doi:, 10.1016/j.chembiol.2019.06.001. PMID:31257183[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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