7l9x

From Proteopedia

(Difference between revisions)

Revision as of 05:33, 28 April 2021

Structure of VPS4B in complex with an allele-specific covalent inhibitor

Structural highlights

7l9x is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Gene:	VPS4B, SKD1, VPS42, MIG1 (HUMAN)
Activity:	Vesicle-fusing ATPase, with EC number 3.6.4.6
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[VPS4B_HUMAN] Involved in late steps of the endosomal multivesicular bodies (MVB) pathway. Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly, possibly in combination with membrane fission. Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. In conjunction with the ESCRT machinery also appears to function in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and enveloped virus budding (HIV-1 and other lentiviruses).^[1] ^[2] ^[3]

Publication Abstract from PubMed

The structural conservation across the AAA (ATPases associated with diverse cellular activities) protein family makes designing selective chemical inhibitors challenging. Here, we identify a triazolopyridine-based fragment that binds the AAA domain of human katanin, a microtubule-severing protein. We have developed a model for compound binding and designed ASPIR-1 (allele-specific, proximity-induced reactivity-based inhibitor-1), a cell-permeable compound that selectively inhibits katanin with an engineered cysteine mutation. Only in cells expressing mutant katanin does ASPIR-1 treatment increase the accumulation of CAMSAP2 at microtubule minus ends, confirming specific on-target cellular activity. Importantly, ASPIR-1 also selectively inhibits engineered cysteine mutants of human VPS4B and FIGL1-AAA proteins, involved in organelle dynamics and genome stability, respectively. Structural studies confirm our model for compound binding at the AAA ATPase site and the proximity-induced reactivity-based inhibition. Together, our findings suggest a chemical genetics approach to decipher AAA protein functions across essential cellular processes and to test hypotheses for developing therapeutics.

A chemical genetics approach to examine the functions of AAA proteins.,Cupido T, Jones NH, Grasso MJ, Pisa R, Kapoor TM Nat Struct Mol Biol. 2021 Mar 29. pii: 10.1038/s41594-021-00575-9. doi:, 10.1038/s41594-021-00575-9. PMID:33782614^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Scheuring S, Rohricht RA, Schoning-Burkhardt B, Beyer A, Muller S, Abts HF, Kohrer K. Mammalian cells express two VPS4 proteins both of which are involved in intracellular protein trafficking. J Mol Biol. 2001 Sep 21;312(3):469-80. PMID:11563910 doi:10.1006/jmbi.2001.4917
↑ von Schwedler UK, Stuchell M, Muller B, Ward DM, Chung HY, Morita E, Wang HE, Davis T, He GP, Cimbora DM, Scott A, Krausslich HG, Kaplan J, Morham SG, Sundquist WI. The protein network of HIV budding. Cell. 2003 Sep 19;114(6):701-13. PMID:14505570
↑ Lata S, Schoehn G, Jain A, Pires R, Piehler J, Gottlinger HG, Weissenhorn W. Helical structures of ESCRT-III are disassembled by VPS4. Science. 2008 Sep 5;321(5894):1354-7. doi: 10.1126/science.1161070. Epub 2008 Aug, 7. PMID:18687924 doi:10.1126/science.1161070
↑ Cupido T, Jones NH, Grasso MJ, Pisa R, Kapoor TM. A chemical genetics approach to examine the functions of AAA proteins. Nat Struct Mol Biol. 2021 Mar 29. pii: 10.1038/s41594-021-00575-9. doi:, 10.1038/s41594-021-00575-9. PMID:33782614 doi:http://dx.doi.org/10.1038/s41594-021-00575-9

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7l9x"

@@ Line 1: / Line 1: @@
 ==Structure of VPS4B in complex with an allele-specific covalent inhibitor==
-<StructureSection load='7l9x' size='340' side='right'caption='[[7l9x]]' scene=''>
+<StructureSection load='7l9x' size='340' side='right'caption='[[7l9x]], [[Resolution|resolution]] 2.81&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7L9X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7L9X FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7l9x]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7L9X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7L9X 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=7l9x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7l9x OCA], [https://pdbe.org/7l9x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7l9x RCSB], [https://www.ebi.ac.uk/pdbsum/7l9x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7l9x ProSAT]</span></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=XQV:N-{3-[(8-phenyl[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino]phenyl}propanamide'>XQV</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">VPS4B, SKD1, VPS42, MIG1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Vesicle-fusing_ATPase Vesicle-fusing ATPase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.4.6 3.6.4.6] </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=7l9x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7l9x OCA], [https://pdbe.org/7l9x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7l9x RCSB], [https://www.ebi.ac.uk/pdbsum/7l9x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7l9x ProSAT]</span></td></tr>
 </table>
+== Function ==
+[[https://www.uniprot.org/uniprot/VPS4B_HUMAN VPS4B_HUMAN]] Involved in late steps of the endosomal multivesicular bodies (MVB) pathway. Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly, possibly in combination with membrane fission. Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. In conjunction with the ESCRT machinery also appears to function in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and enveloped virus budding (HIV-1 and other lentiviruses).<ref>PMID:11563910</ref> <ref>PMID:14505570</ref> <ref>PMID:18687924</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The structural conservation across the AAA (ATPases associated with diverse cellular activities) protein family makes designing selective chemical inhibitors challenging. Here, we identify a triazolopyridine-based fragment that binds the AAA domain of human katanin, a microtubule-severing protein. We have developed a model for compound binding and designed ASPIR-1 (allele-specific, proximity-induced reactivity-based inhibitor-1), a cell-permeable compound that selectively inhibits katanin with an engineered cysteine mutation. Only in cells expressing mutant katanin does ASPIR-1 treatment increase the accumulation of CAMSAP2 at microtubule minus ends, confirming specific on-target cellular activity. Importantly, ASPIR-1 also selectively inhibits engineered cysteine mutants of human VPS4B and FIGL1-AAA proteins, involved in organelle dynamics and genome stability, respectively. Structural studies confirm our model for compound binding at the AAA ATPase site and the proximity-induced reactivity-based inhibition. Together, our findings suggest a chemical genetics approach to decipher AAA protein functions across essential cellular processes and to test hypotheses for developing therapeutics.
+A chemical genetics approach to examine the functions of AAA proteins.,Cupido T, Jones NH, Grasso MJ, Pisa R, Kapoor TM Nat Struct Mol Biol. 2021 Mar 29. pii: 10.1038/s41594-021-00575-9. doi:, 10.1038/s41594-021-00575-9. PMID:33782614<ref>PMID:33782614</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 7l9x" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Cupido T]]
+[[Category: Vesicle-fusing ATPase]]
-[[Category: Grasso M]]
+[[Category: Cupido, T]]
-[[Category: Kapoor TM]]
+[[Category: Grasso, M]]
+[[Category: Kapoor, T M]]
+[[Category: Aaa superfamily]]
+[[Category: Atpase]]
+[[Category: Chemical inhibitor]]
+[[Category: Hydrolase]]
+[[Category: Protein transport]]

7l9x

From Proteopedia

Revision as of 05:33, 28 April 2021

Structure of VPS4B in complex with an allele-specific covalent inhibitor

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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