3bps

OverviewOverview

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.

About this StructureAbout this Structure

3BPS is a Protein complex structure of sequences from Homo sapiens with as ligand. Known structural/functional Site: . Full crystallographic information is available from OCA.

ReferenceReference

Molecular basis for LDL receptor recognition by PCSK9., Kwon HJ, Lagace TA, McNutt MC, Horton JD, Deisenhofer J, Proc Natl Acad Sci U S A. 2008 Feb 4;. PMID:18250299

Page seeded by OCA on Wed Feb 13 08:23:55 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA