3BPS

PCSK9:EGF-A complex

3BPS の概要

• エントリーDOI: 10.2210/pdb3bps/pdb
• 分子名称: Proprotein convertase subtilisin/kexin type 9, Low-density lipoprotein receptor, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: pcsk9, ldl receptor, autocatalytic cleavage, cholesterol metabolism, disease mutation, glycoprotein, hydrolase, lipid metabolism, phosphoprotein, protease, secreted, serine protease, steroid metabolism, zymogen, coated pit, egf-like domain, endocytosis, host-virus interaction, lipid transport, membrane, transmembrane, transport, hydrolase-lipid transport complex, hydrolase/lipid transport
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Secreted: Q8NBP7 Q8NBP7; Cell membrane; Single-pass type I membrane protein: P01130
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 77857.85

構造登録者

Kwon, H.J. (登録日: 2007-12-19, 公開日: 2008-02-12, 最終更新日: 2024-10-30)

主引用文献

Kwon, H.J.,Lagace, T.A.,McNutt, M.C.,Horton, J.D.,Deisenhofer, J.
Molecular basis for LDL receptor recognition by PCSK9.
Proc.Natl.Acad.Sci.Usa, 105:1820-1825, 2008

PubMed Abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) posttranslationally regulates hepatic low-density lipoprotein receptors (LDLRs) by binding to LDLRs on the cell surface, leading to their degradation. The binding site of PCSK9 has been localized to the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR. Here, we describe the crystal structure of a complex between PCSK9 and the EGF-A domain of the LDLR. The binding site for the LDLR EGF-A domain resides on the surface of PCSK9's subtilisin-like catalytic domain containing Asp-374, a residue for which a gain-of-function mutation (Asp-374-Tyr) increases the affinity of PCSK9 toward LDLR and increases plasma LDL-cholesterol (LDL-C) levels in humans. The binding surface on PCSK9 is distant from its catalytic site, and the EGF-A domain makes no contact with either the C-terminal domain or the prodomain. Point mutations in PCSK9 that altered key residues contributing to EGF-A binding (Arg-194 and Phe-379) greatly diminished binding to the LDLR's extracellular domain. The structure of PCSK9 in complex with the LDLR EGF-A domain defines potential therapeutic target sites for blocking agents that could interfere with this interaction in vivo, thereby increasing LDLR function and reducing plasma LDL-C levels.

PubMed: 18250299
DOI: 10.1073/pnas.0712064105

実験手法

X-RAY DIFFRACTION (2.41 Å)