3SQO

PCSK9 J16 Fab complex

Summary for 3SQO

• Entry DOI: 10.2210/pdb3sqo/pdb
• Descriptor: Proprotein convertase subtilisin/kexin type 9, J16 Heavy chain, J16 Light chain, ... (5 entities in total)
• Functional Keywords: cholesterol regulation, ldlr, hydrolase-immune system complex, hydrolase/immune system
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: Q8NBP7 Q8NBP7
• Total number of polymer chains: 4
• Total formula weight: 118530.84

Authors

Strop, P. (deposition date: 2011-07-05, release date: 2012-05-16)

Primary citation

Liang, H.,Chaparro-Riggers, J.,Strop, P.,Geng, T.,Sutton, J.E.,Tsai, D.,Bai, L.,Abdiche, Y.,Dilley, J.,Yu, J.,Wu, S.,Chin, S.M.,Lee, N.A.,Rossi, A.,Lin, J.C.,Rajpal, A.,Pons, J.,Shelton, D.L.
Proprotein convertase substilisin/kexin type 9 antagonism reduces low-density lipoprotein cholesterol in statin-treated hypercholesterolemic nonhuman primates.
J.Pharmacol.Exp.Ther., 340:228-236, 2012

PubMed Abstract: Proprotein convertase substilisin/kexin type 9 (PCSK9) promotes the degradation of low-density lipoprotein (LDL) receptor (LDLR) and thereby increases serum LDL-cholesterol (LDL-C). We have developed a humanized monoclonal antibody that recognizes the LDLR binding domain of PCSK9. This antibody, J16, and its precursor mouse antibody, J10, potently inhibit PCSK9 binding to the LDLR extracellular domain and PCSK9-mediated down-regulation of LDLR in vitro. In vivo, J10 effectively reduces serum cholesterol in C57BL/6 mice fed normal chow. J16 reduces LDL-C in healthy and diet-induced hypercholesterolemic cynomologous monkeys, but does not significantly affect high-density lipoprotein-cholesterol. Furthermore, J16 greatly lowered LDL-C in hypercholesterolemic monkeys treated with the HMG-CoA reductase inhibitor simvastatin. Our data demonstrate that anti-PCSK9 antibody is a promising LDL-C-lowering agent that is both efficacious and potentially additive to current therapies.

PubMed: 22019884
DOI: 10.1124/jpet.111.187419

Experimental method

X-RAY DIFFRACTION (2.7 Å)