4ogy | pdb_00004ogy
Crystal structure of Fab DX-2930 in complex with human plasma kallikrein at 2.1 Angstrom resolution
Structural highlights
DiseaseKLKB1_HUMAN Defects in KLKB1 are the cause of prekallikrein deficiency (PKK deficiency) [MIM:612423; also known as Fletcher factor deficiency. This disorder is a blood coagulation defect. FunctionKLKB1_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. Publication Abstract from PubMedPlasma 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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