View source for 2w12


==High-resolution crystal structure of the P-I snake venom metalloproteinase BaP1 in complex with a peptidomimetic: insights into inhibitor binding==
<StructureSection load='2w12' size='340' side='right'caption='[[2w12]], [[Resolution|resolution]] 1.46&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2w12]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Bothrops_asper Bothrops asper]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2W12 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2W12 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]] 1.46&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</scene>, <scene name='pdbligand=WR2:(2R,3R)-N^1^-[(1S)-2,2-DIMETHYL-1-(METHYLCARBAMOYL)PROPYL]-N^4^-HYDROXY-2-(2-METHYLPROPYL)-3-{[(1,3-THIAZOL-2-YLCARBONYL)AMINO]METHYL}BUTANEDIAMIDE'>WR2</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=2w12 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2w12 OCA], [https://pdbe.org/2w12 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2w12 RCSB], [https://www.ebi.ac.uk/pdbsum/2w12 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2w12 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/VM1B1_BOTAS VM1B1_BOTAS] Zinc metalloprotease that exhibits a weak hemorrhagic activity (with a minimum hemorrhagic dose of 20 ug by intradermal and intramuscular injection into mice). The basal membrane components collagen (all chains of type IV) (COL4A4), laminin and nidogen are all degraded by this toxin (PubMed:23385358). Rapidly degrades the Aalpha-chain (FGA) of fibrinogen, and later on, degrades the Bbeta-chain (FGB) of fibrinogen (PubMed:7778126). Also activates the complement system, and induces rat neutrophil chemotaxis (PubMed:11200361). Induces edema in mouse food pad and a mild myotoxicity (PubMed:7778126).<ref>PMID:11200361</ref> <ref>PMID:20600221</ref> <ref>PMID:23385358</ref> <ref>PMID:7778126</ref> 
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/w1/2w12_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2w12 ConSurf].
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== Publication Abstract from PubMed ==
BaP1, a zinc-dependent endopeptidase belonging to the P-I class of snake venom metalloproteinases, exerts multiple tissue-damaging activities, leading to hemorrhage, myonecrosis, dermonecrosis, blistering, and edema. Interestingly, this metalloproteinase shows a high degree of structural homology with the catalytic domain of human adamalysins and matrix metalloproteinases, especially at the strictly conserved zinc binding motif and the so-called Met turn. This highlights BaP1 as an interesting model concerning inhibitor design for several medicinally important metalloproteinases, such as tumor necrosis factor alpha converting enzyme. Here, we report the first crystal structure of BaP1 complexed with a peptidomimetic inhibitor. Suitable crystals were obtained at four different pH values (4.6, 6.5, 7.5, and 8.0), and four high-resolution structures (1.46, 1.14, 1.08, and 1.05 A) were established. These structures and the detailed analysis of the structure-activity relationship of the bound inhibitor form a basis for the design of potent BaP1 inhibitors. The latter can be used for the treatment of local pathological effects caused by snake bites, mainly due to metalloproteinases such as BaP1. Besides, the high-resolution structure is an excellent starting point for the rational development of inhibitors for human metalloproteinases. The finding of a flexible loop region may have a great impact on further studies as to date little is known about the structural dependencies of the hemorrhagic activity of snake venom metalloproteinases.

High-Resolution Crystal Structure of the Snake Venom Metalloproteinase BaP1 Complexed with a Peptidomimetic: Insight into Inhibitor Binding.,Lingott T, Schleberger C, Gutierrez JM, Merfort I Biochemistry. 2009 Jun 15. PMID:19485419<ref>PMID:19485419</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Bothrops asper]]
[[Category: Large Structures]]
[[Category: Gutierrez JM]]
[[Category: Lingott TJ]]
[[Category: Merfort I]]
[[Category: Schleberger C]]