3H42

Crystal structure of PCSK9 in complex with Fab from LDLR competitive antibody

Summary for 3H42

• Entry DOI: 10.2210/pdb3h42/pdb
• Descriptor: Proprotein convertase subtilisin/kexin type 9, Fab from LDLR competitive antibody: Light chain, Fab from LDLR competitive antibody: Heavy chain, ... (6 entities in total)
• Functional Keywords: hydrolase, protein fab complex, autocatalytic cleavage, cholesterol metabolism, disease mutation, disulfide bond, glycoprotein, lipid metabolism, phosphoprotein, protease, secreted, serine protease, steroid metabolism, zymogen, 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: 119575.64

Authors

Piper, D.E.,Walker, N.P.C.,Romanow, W.G.,Thibault, S.T.,Tsai, M.M.,Yang, E. (deposition date: 2009-04-17, release date: 2009-05-05, Last modification date: 2024-10-30)

Primary citation

Chan, J.C.,Piper, D.E.,Cao, Q.,Liu, D.,King, C.,Wang, W.,Tang, J.,Liu, Q.,Higbee, J.,Xia, Z.,Di, Y.,Shetterly, S.,Arimura, Z.,Salomonis, H.,Romanow, W.G.,Thibault, S.T.,Zhang, R.,Cao, P.,Yang, X.P.,Yu, T.,Lu, M.,Retter, M.W.,Kwon, G.,Henne, K.,Pan, O.,Tsai, M.M.,Fuchslocher, B.,Yang, E.,Zhou, L.,Lee, K.J.,Daris, M.,Sheng, J.,Wang, Y.,Shen, W.D.,Yeh, W.C.,Emery, M.,Walker, N.P.,Shan, B.,Schwarz, M.,Jackson, S.M.
From the Cover: A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates.
Proc.Natl.Acad.Sci.USA, 106:9820-9825, 2009

PubMed Abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates serum LDL cholesterol (LDL-C) by interacting with the LDL receptor (LDLR) and is an attractive therapeutic target for LDL-C lowering. We have generated a neutralizing anti-PCSK9 antibody, mAb1, that binds to an epitope on PCSK9 adjacent to the region required for LDLR interaction. In vitro, mAb1 inhibits PCSK9 binding to the LDLR and attenuates PCSK9-mediated reduction in LDLR protein levels, thereby increasing LDL uptake. A combination of mAb1 with a statin increases LDLR levels in HepG2 cells more than either treatment alone. In wild-type mice, mAb1 increases hepatic LDLR protein levels approximately 2-fold and lowers total serum cholesterol by up to 36%: this effect is not observed in LDLR(-/-) mice. In cynomolgus monkeys, a single injection of mAb1 reduces serum LDL-C by 80%, and a significant decrease is maintained for 10 days. We conclude that anti-PCSK9 antibodies may be effective therapeutics for treating hypercholesterolemia.

PubMed: 19443683
DOI: 10.1073/pnas.0903849106

Experimental method

X-RAY DIFFRACTION (2.3 Å)