Preparing your results

Our searching services are busy right now. Your search will reload in five seconds.

Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

Molecular basis for LDL receptor recognition by PCSK9.

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 ID: 18250299


  • Kwon HJ
  • Lagace TA
  • McNutt MC
  • Horton JD
  • Deisenhofer J


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

February 12, 2008

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM08014
  • Agency: NHLBI NIH HHS, Id: HL-20948
  • Agency: NHLBI NIH HHS, Id: HL-38049

Mesh Terms

  • Binding Sites
  • Cell Line
  • Epidermal Growth Factor
  • Humans
  • Hydrogen-Ion Concentration
  • Lipoproteins, LDL
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Proprotein Convertases
  • Protein Binding
  • Protein Conformation
  • Receptors, LDL
  • Serine Endopeptidases