 |
PDBsum entry 3bps
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hydrolase/lipid transport
|
PDB id
|
|
|
|
3bps
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Molecular basis for ldl receptor recognition by pcsk9.
|
|
|
Authors
|
|
H.J.Kwon,
T.A.Lagace,
M.C.Mcnutt,
J.D.Horton,
J.Deisenhofer.
|
|
|
Ref.
|
|
Proc Natl Acad Sci U S A, 2008,
105,
1820-1825.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
|
Figure 1.
The PCSK9:EGF-A complex. (A) PCSK9, with the prodomain
(magenta), the subtilisin-like catalytic domain (green), and the
C-terminal domain (brown), and the EGF-A domain of LDLR (blue)
is represented as a ribbon diagram. The bound calcium ion within
the EGF-A domain is shown as a red sphere. (B) Superposition of
the PCSK9:EGF-A complex and apo-PCSK9. The PCSK9:EGF-A complex
is shown with PCSK9 in green, EGF-A in blue, and bound calcium
as a red sphere. Apo-PCSK9 is shown in red. (C) The apo-PCSK9
(Protein Data Bank ID code 2P4E, blue; Protein Data Bank ID code
2PMW, cyan; Protein Data Bank ID code 2QTW, magenta) structures
superimposed onto the PCSK9:EGF-A complex [carbon, gray (PCSK9)
or yellow (EGF-A); nitrogen, blue; oxygen, red]. Arg-194 from
PCSK9 forms a salt bridge with Asp-310 of EGF-A, breaking an
intramolecular salt bridge with Glu-197.
|
|
Figure 3.
Mutations in PCSK9 and LDLR. (A) The gain-of-function
mutation Asp-374–Tyr in PCSK9 increases binding to LDLR.
Asp-374 in PCSK9 modeled as tyrosine (gray) is in position to
hydrogen bond to His-306 of LDLR. (B) The FH mutation
His-306–Tyr in LDLR. His-306 in LDLR modeled as tyrosine
(gray) is in position to hydrogen bond to Asp-374 of PCSK9. (C)
Model for full-length LDLR-ECD bound to PCSK9. The EGF-A domain
(blue) of the LDLR-ECD (cyan) at acidic pH and the PCKSK9:EGF-A
complex were superimposed. PCSK9 (prodomain, magenta;
subtilisin-like catalytic domain, green; C-terminal domain,
brown) binds on the outside surface of LDLR and would not
interfere with the interaction of ligand binding modules R4 and
R5 with the β-propeller domain.
|
|
|
|
|
|
|
|
|
|
