PDBsum entry 3bps

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protein metals Protein-protein interface(s) links
Hydrolase/lipid transport PDB id
Protein chains
92 a.a. *
435 a.a. *
41 a.a. *
Waters ×129
* Residue conservation analysis
PDB id:
Name: Hydrolase/lipid transport
Title: Pcsk9:egf-a complex
Structure: Proprotein convertase subtilisin/kexin type 9. Chain: p. Fragment: prodomain, unp residues 53-152. Synonym: proprotein convertase pc9, subtilisin/kexin-like p pc9, neural apoptosis-regulated convertase 1, narc-1. Engineered: yes. Proprotein convertase subtilisin/kexin type 9. Chain: a. Fragment: catalytic domain, unp residues 153-692.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pcsk9, narc1. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: ldlr. Expression_system_taxid: 562
2.41Å     R-factor:   0.205     R-free:   0.240
Authors: H.J.Kwon
Key ref:
H.J.Kwon et al. (2008). Molecular basis for LDL receptor recognition by PCSK9. Proc Natl Acad Sci U S A, 105, 1820-1825. PubMed id: 18250299 DOI: 10.1073/pnas.0712064105
19-Dec-07     Release date:   12-Feb-08    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q8NBP7  (PCSK9_HUMAN) -  Proprotein convertase subtilisin/kexin type 9
692 a.a.
92 a.a.
Protein chain
Pfam   ArchSchema ?
Q8NBP7  (PCSK9_HUMAN) -  Proprotein convertase subtilisin/kexin type 9
692 a.a.
435 a.a.*
Protein chain
Pfam   ArchSchema ?
P01130  (LDLR_HUMAN) -  Low-density lipoprotein receptor
860 a.a.
41 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     calcium ion binding     2 terms  


DOI no: 10.1073/pnas.0712064105 Proc Natl Acad Sci U S A 105:1820-1825 (2008)
PubMed id: 18250299  
Molecular basis for LDL receptor recognition by PCSK9.
H.J.Kwon, T.A.Lagace, M.C.McNutt, J.D.Horton, J.Deisenhofer.
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.
  Selected figure(s)  
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.
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22679642 N.G.Seidah, and A.Prat (2012).
The biology and therapeutic targeting of the proprotein convertases.
  Nat Rev Drug Discov, 11, 367-383.  
21352602 R.J.Konrad, J.S.Troutt, and G.Cao (2011).
Effects of currently prescribed LDL-C-lowering drugs on PCSK9 and implications for the next generation of LDL-C-lowering agents.
  Lipids Health Dis, 10, 38.  
19571328 G.Dubuc, M.Tremblay, G.Paré, H.Jacques, J.Hamelin, S.Benjannet, L.Boulet, J.Genest, L.Bernier, N.G.Seidah, and J.Davignon (2010).
A new method for measurement of total plasma PCSK9: clinical applications.
  J Lipid Res, 51, 140-149.  
20498851 N.Gupta, N.Fisker, M.C.Asselin, M.Lindholm, C.Rosenbohm, H.Ørum, J.Elmén, N.G.Seidah, and E.M.Straarup (2010).
A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo.
  PLoS One, 5, e10682.  
19196236 C.J.Duff, M.J.Scott, I.T.Kirby, S.E.Hutchinson, S.L.Martin, and N.M.Hooper (2009).
Antibody-mediated disruption of the interaction between PCSK9 and the low-density lipoprotein receptor.
  Biochem J, 419, 577-584.  
19688294 D.Lindholm, B.C.Bornhauser, and L.Korhonen (2009).
Mylip makes an Idol turn into regulation of LDL receptor.
  Cell Mol Life Sci, 66, 3399-3402.  
19443683 J.C.Chan, D.E.Piper, Q.Cao, D.Liu, C.King, W.Wang, J.Tang, Q.Liu, J.Higbee, Z.Xia, Y.Di, S.Shetterly, Z.Arimura, H.Salomonis, W.G.Romanow, S.T.Thibault, R.Zhang, P.Cao, X.P.Yang, T.Yu, M.Lu, M.W.Retter, G.Kwon, K.Henne, O.Pan, M.M.Tsai, B.Fuchslocher, E.Yang, L.Zhou, K.J.Lee, M.Daris, J.Sheng, Y.Wang, W.D.Shen, W.C.Yeh, M.Emery, N.P.Walker, B.Shan, M.Schwarz, and S.M.Jackson (2009).
A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates.
  Proc Natl Acad Sci U S A, 106, 9820-9825.
PDB code: 3h42
19020338 J.D.Horton, J.C.Cohen, and H.H.Hobbs (2009).
PCSK9: a convertase that coordinates LDL catabolism.
  J Lipid Res, 50, S172-S177.  
19373230 J.E.Lee, M.L.Fusco, and E.Ollmann Saphire (2009).
An efficient platform for screening expression and crystallization of glycoproteins produced in human cells.
  Nat Protoc, 4, 592-604.  
19191301 M.Abifadel, J.P.Rabès, M.Devillers, A.Munnich, D.Erlich, C.Junien, M.Varret, and C.Boileau (2009).
Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease.
  Hum Mutat, 30, 520-529.  
19224862 M.C.McNutt, H.J.Kwon, C.Chen, J.R.Chen, J.D.Horton, and T.A.Lagace (2009).
Antagonism of secreted PCSK9 increases low density lipoprotein receptor expression in HepG2 cells.
  J Biol Chem, 284, 10561-10570.
PDB codes: 3gcw 3gcx
19063703 N.G.Seidah (2009).
PCSK9 as a therapeutic target of dyslipidemia.
  Expert Opin Ther Targets, 13, 19-28.  
19104240 S.Kovac, A.Shulkes, and G.S.Baldwin (2009).
Peptide processing and biology in human disease.
  Curr Opin Endocrinol Diabetes Obes, 16, 79-85.  
19635789 S.Poirier, G.Mayer, V.Poupon, P.S.McPherson, R.Desjardins, K.Ly, M.C.Asselin, R.Day, F.J.Duclos, M.Witmer, R.Parker, A.Prat, and N.G.Seidah (2009).
Dissection of the endogenous cellular pathways of PCSK9-induced low density lipoprotein receptor degradation: evidence for an intracellular route.
  J Biol Chem, 284, 28856-28864.  
18354138 A.Grefhorst, M.C.McNutt, T.A.Lagace, and J.D.Horton (2008).
Plasma PCSK9 preferentially reduces liver LDL receptors in mice.
  J Lipid Res, 49, 1303-1311.  
18375913 A.S.Peterson, L.G.Fong, and S.G.Young (2008).
PCSK9 function and physiology.
  J Lipid Res, 49, 1152-1156.  
18666258 A.Zaid, A.Roubtsova, R.Essalmani, J.Marcinkiewicz, A.Chamberland, J.Hamelin, M.Tremblay, H.Jacques, W.Jin, J.Davignon, N.G.Seidah, and A.Prat (2008).
Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration.
  Hepatology, 48, 646-654.  
18753623 D.W.Zhang, R.Garuti, W.J.Tang, J.C.Cohen, and H.H.Hobbs (2008).
Structural requirements for PCSK9-mediated degradation of the low-density lipoprotein receptor.
  Proc Natl Acad Sci U S A, 105, 13045-13050.  
18631360 J.Cameron, ..L.Holla, K.E.Berge, M.A.Kulseth, T.Ranheim, T.P.Leren, and J.K.Laerdahl (2008).
Investigations on the evolutionary conservation of PCSK9 reveal a functionally important protrusion.
  FEBS J, 275, 4121-4133.  
18672372 P.Costet, M.Krempf, and B.Cariou (2008).
PCSK9 and LDL cholesterol: unravelling the target to design the bullet.
  Trends Biochem Sci, 33, 426-434.  
18498363 T.Dewpura, A.Raymond, J.Hamelin, N.G.Seidah, M.Mbikay, M.Chrétien, and J.Mayne (2008).
PCSK9 is phosphorylated by a Golgi casein kinase-like kinase ex vivo and circulates as a phosphoprotein in humans.
  FEBS J, 275, 3480-3493.  
22517340 , (0).
  , (), 0.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.