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The | ==Crystal structure of Fab DX-2930 in complex with human plasma kallikrein at 2.4 Angstrom resolution== | ||
<StructureSection load='4ogx' size='340' side='right'caption='[[4ogx]], [[Resolution|resolution]] 2.40Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4ogx]] is a 3 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=4OGX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OGX 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]] 2.4Å</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></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=4ogx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ogx OCA], [https://pdbe.org/4ogx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ogx RCSB], [https://www.ebi.ac.uk/pdbsum/4ogx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ogx ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/KLKB1_HUMAN KLKB1_HUMAN] Defects in KLKB1 are the cause of prekallikrein deficiency (PKK deficiency) [MIM:[https://omim.org/entry/612423 612423]; also known as Fletcher factor deficiency. This disorder is a blood coagulation defect. | |||
== Function == | |||
[https://www.uniprot.org/uniprot/KLKB1_HUMAN KLKB1_HUMAN] The enzyme cleaves Lys-Arg and Arg-Ser bonds. It activates, in a reciprocal reaction, factor XII after its binding to a negatively charged surface. It also releases bradykinin from HMW kininogen and may also play a role in the renin-angiotensin system by converting prorenin into renin. | |||
<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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4ogx" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Kallikrein 3D structures|Kallikrein 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Abendroth J]] | |||
[[Category: Clifton MC]] | |||
[[Category: Edwards TE]] | |||
[[Category: Ladner R]] | |||
[[Category: Nixon A]] | |||