View source for 4pub


==Crystal structure of Fab DX-2930==
<StructureSection load='4pub' size='340' side='right'caption='[[4pub]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4pub]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PUB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PUB 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]] 1.75&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</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=4pub FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pub OCA], [https://pdbe.org/4pub PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4pub RCSB], [https://www.ebi.ac.uk/pdbsum/4pub PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4pub ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/S6C4R2_HUMAN S6C4R2_HUMAN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Plasma kallikrein (pKal) proteolytically cleaves high molecular weight kininogen (HMWK) to generate the potent vasodilator, and pro-inflammatory peptide, bradykinin. pKal activity is tightly regulated in healthy individuals by the serpin C1-Inhibitor (C1-INH), but individuals with hereditary angioedema (HAE) are deficient in C1-INH and consequently exhibit excessive bradykinin generation that in turn causes debilitating and potentially fatal swelling attacks. To develop a potential therapeutic agent for HAE and other pKal-mediated disorders, we used phage display to discover a fully human IgG1 monoclonal antibody (DX-2930) against pKal. In vitro experiments demonstrated that DX-2930 potently inhibits active pKal (Ki = 0.120 +/- 0.005 nM), but does not target either the zymogen (prekallikrein) or any other serine protease tested. These findings are supported by a 2.1 angstrom resolution crystal structure of pKal complexed to a DX-2930 Fab construct, which establishes that the pKal active site is fully occluded by the antibody. DX-2930 injected subcutaneously into cynomolgus monkeys exhibited a long half-life (t1/2 ~ 12.5 days) and blocked HMWK proteolysis in activated plasma in a dose and time-dependent manner. Furthermore, subcutaneous DX-2930 reduced carrageenan-induced paw edema in rats. A potent and long acting inhibitor of pKal activity could be an effective treatment option for pKal-mediated diseases, such as HAE.

Inhibition of Plasma Kallikrein by a Highly Specific, Active Site Blocking Antibody.,Kenniston JA, Faucette RR, Martik D, Comeau SR, Lindberg AP, Kopacz KJ, Conley GP, Chen J, Viswanathan M, Kastrapeli N, Cosic J, Mason S, DiLeo M, Abendroth J, Kuzmic P, Ladner RC, Edwards TE, TenHoor C, Adelman BA, Nixon AE, Sexton DJ J Biol Chem. 2014 Jun 26. pii: jbc.M114.569061. PMID:24970892<ref>PMID:24970892</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4pub" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Abendroth J]]
[[Category: Edwards TE]]
[[Category: Ladner R]]
[[Category: Nixon A]]