5dl1: Difference between revisions
New page: '''Unreleased structure''' The entry 5dl1 is ON HOLD Authors: Vielberg, M.-T., Groll, M. Description: ClpP from Staphylococcus aureus in complex with AV145 [[Category: Unreleased Struc... |
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==ClpP from Staphylococcus aureus in complex with AV145== | |||
<StructureSection load='5dl1' size='340' side='right'caption='[[5dl1]], [[Resolution|resolution]] 3.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5dl1]] is a 14 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DL1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5DL1 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]] 3Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5C2:1-(PROPAN-2-YL)-N-{[2-(THIOPHEN-2-YL)-1,3-OXAZOL-4-YL]METHYL}-1H-PYRAZOLO[3,4-B]PYRIDINE-5-CARBOXAMIDE'>5C2</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=5dl1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dl1 OCA], [https://pdbe.org/5dl1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5dl1 RCSB], [https://www.ebi.ac.uk/pdbsum/5dl1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5dl1 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CLPP_STAA8 CLPP_STAA8] Cleaves peptides in various proteins in a process that requires ATP hydrolysis. Has a chymotrypsin-like activity. Plays a major role in the degradation of misfolded proteins (By similarity). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Caseinolytic protease P (ClpP) is an important regulator of Staphylococcus aureus pathogenesis. A high-throughput screening for inhibitors of ClpP peptidase activity led to the identification of the first non-covalent binder for this enzyme class. Co-crystallization of the small molecule with S. aureus ClpP revealed a novel binding mode: Because of the rotation of the conserved residue proline 125, ClpP is locked in a defined conformational state, which results in distortion of the catalytic triad and inhibition of the peptidase activity. Based on these structural insights, the molecule was optimized by rational design and virtual screening, resulting in derivatives exceeding the potency of previous ClpP inhibitors. Strikingly, the conformational lock is overturned by binding of ClpX, an associated chaperone that enables proteolysis by substrate unfolding in the ClpXP complex. Thus, regulation of inhibitor binding by associated chaperones is an unexpected mechanism important for ClpP drug development. | |||
Reversible Inhibitors Arrest ClpP in a Defined Conformational State that Can Be Revoked by ClpX Association.,Pahl A, Lakemeyer M, Vielberg MT, Hackl MW, Vomacka J, Korotkov VS, Stein ML, Fetzer C, Lorenz-Baath K, Richter K, Waldmann H, Groll M, Sieber SA Angew Chem Int Ed Engl. 2015 Nov 13. doi: 10.1002/anie.201507266. PMID:26566002<ref>PMID:26566002</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5dl1" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
==See Also== | |||
*[[Clp protease 3D structures|Clp protease 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Staphylococcus aureus]] | |||
[[Category: Groll M]] | |||
[[Category: Vielberg M-T]] | |||
Latest revision as of 00:47, 29 June 2023
ClpP from Staphylococcus aureus in complex with AV145ClpP from Staphylococcus aureus in complex with AV145
Structural highlights
FunctionCLPP_STAA8 Cleaves peptides in various proteins in a process that requires ATP hydrolysis. Has a chymotrypsin-like activity. Plays a major role in the degradation of misfolded proteins (By similarity). Publication Abstract from PubMedCaseinolytic protease P (ClpP) is an important regulator of Staphylococcus aureus pathogenesis. A high-throughput screening for inhibitors of ClpP peptidase activity led to the identification of the first non-covalent binder for this enzyme class. Co-crystallization of the small molecule with S. aureus ClpP revealed a novel binding mode: Because of the rotation of the conserved residue proline 125, ClpP is locked in a defined conformational state, which results in distortion of the catalytic triad and inhibition of the peptidase activity. Based on these structural insights, the molecule was optimized by rational design and virtual screening, resulting in derivatives exceeding the potency of previous ClpP inhibitors. Strikingly, the conformational lock is overturned by binding of ClpX, an associated chaperone that enables proteolysis by substrate unfolding in the ClpXP complex. Thus, regulation of inhibitor binding by associated chaperones is an unexpected mechanism important for ClpP drug development. Reversible Inhibitors Arrest ClpP in a Defined Conformational State that Can Be Revoked by ClpX Association.,Pahl A, Lakemeyer M, Vielberg MT, Hackl MW, Vomacka J, Korotkov VS, Stein ML, Fetzer C, Lorenz-Baath K, Richter K, Waldmann H, Groll M, Sieber SA Angew Chem Int Ed Engl. 2015 Nov 13. doi: 10.1002/anie.201507266. PMID:26566002[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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