View source for 7zbv


==Crystal structure of the peptidase domain of collagenase G from Clostridium histolyticum in complex with a diphosphonate-based inhibitor==
<StructureSection load='7zbv' size='340' side='right'caption='[[7zbv]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7zbv]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Hathewaya_histolytica Hathewaya histolytica]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7ZBV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ZBV 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]] 1.95&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=144:TRIS-HYDROXYMETHYL-METHYL-AMMONIUM'>144</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=ITO:[6,7-bis(chloranyl)-3-phosphono-quinoxalin-2-yl]phosphonic+acid'>ITO</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=7zbv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7zbv OCA], [https://pdbe.org/7zbv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7zbv RCSB], [https://www.ebi.ac.uk/pdbsum/7zbv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7zbv ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/COLG_HATHI COLG_HATHI] Clostridial collagenases are among the most efficient degraders of eukaryotic collagen known; saprophytes use collagen as a carbon source while pathogens additionally digest collagen to aid in host colonization. Has both tripeptidylcarboxypeptidase on Gly-X-Y and endopeptidase activities; the endopeptidase cuts within the triple helix region of collagen while tripeptidylcarboxypeptidase successively digests the exposed ends, thus clostridial collagenases can digest large sections of collagen (PubMed:3002446). Active on soluble type I collagen, insoluble collagen, azocoll, soluble PZ-peptide (all collagenase substrates) and gelatin (PubMed:9922257). The full-length protein has collagenase activity, while the in vivo derived C-terminally truncated shorter versions only act on gelatin (PubMed:9922257). In vitro digestion of soluble calf skin collagen fibrils requires both ColG and ColH; ColG forms missing the second collagen-binding domain are also synergistic with ColH, although their overall efficiency is decreased (PubMed:18374061, PubMed:22099748). The activator domain (residues 119-388) and catalytic subdomain (389-670) open and close around substrate using a Gly-rich hinge (387-397), allowing digestion when the protein is closed (PubMed:21947205, PubMed:23703618). Binding of collagen requires Ca(2+) and is inhibited by EGTA; the collagen-binding domain (CBD, S3a plus S3b) specifically recognizes the triple-helical conformation made by 3 collagen protein chains in the triple-helical region (PubMed:11121400). Isolated CBD (S3a plus S3b) binds collagen fibrils and sheets of many tissues (PubMed:11913772).<ref>PMID:11121400</ref> <ref>PMID:11913772</ref> <ref>PMID:18374061</ref> <ref>PMID:18937627</ref> <ref>PMID:21947205</ref> <ref>PMID:22099748</ref> <ref>PMID:23703618</ref> <ref>PMID:24125730</ref> <ref>PMID:28820255</ref> <ref>PMID:3002446</ref> <ref>PMID:9922257</ref> 
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== Publication Abstract from PubMed ==
In view of the worldwide antimicrobial resistance (AMR) threat, new bacterial targets and anti-infective agents are needed. Since important roles in bacterial pathogenesis have been demonstrated for the collagenase H and G (ColH and ColG) from Clostridium histolyticum, collagenase Q1 and A (ColQ1 and ColA) from Bacillus cereus represent attractive antivirulence targets. Furthermore, repurposing FDA-approved drugs may assist to tackle the AMR crisis and was addressed in this work. Here, we report on the discovery of two potent and chemically stable bacterial collagenase inhibitors: synthesized and FDA-approved diphosphonates and hydroxamates. Both classes showed high in vitro activity against the clostridial and bacillary collagenases. The potent diphosphonates reduced B. cereus-mediated detachment and death of cells and Galleria mellonella larvae. The hydroxamates were also tested in a similar manner; they did not have an effect in infection models. This might be due to their fast binding kinetics to bacterial collagenases.

Discovery and Characterization of Synthesized and FDA-Approved Inhibitors of Clostridial and Bacillary Collagenases.,Alhayek A, Abdelsamie AS, Schonauer E, Camberlein V, Hutterer E, Posselt G, Serwanja J, Blochl C, Huber CG, Haupenthal J, Brandstetter H, Wessler S, Hirsch AKH J Med Chem. 2022 Oct 13;65(19):12933-12955. doi: 10.1021/acs.jmedchem.2c00785., Epub 2022 Sep 26. PMID:36154055<ref>PMID:36154055</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 7zbv" style="background-color:#fffaf0;"></div>

==See Also==
*[[Collagenase 3D structures|Collagenase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Hathewaya histolytica]]
[[Category: Large Structures]]
[[Category: Brandstetter H]]
[[Category: Schoenauer E]]