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PDBsum entry 2pmw

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protein ligands Protein-protein interface(s) links
Hydrolase PDB id
2pmw
Jmol
Contents
Protein chains
92 a.a. *
489 a.a. *
Ligands
SO4 ×2
Waters ×215
* Residue conservation analysis
PDB id:
2pmw
Name: Hydrolase
Title: The crystal structure of proprotein convertase subtilisin kexin type 9 (pcsk9)
Structure: Proprotein convertase subtilisin/kexin type 9. Chain: a. Synonym: proprotein convertase pc9, subtilisin/kexin-like protease pc9, neural apoptosis-regulated convertase 1, narc-1. Engineered: yes. Proprotein convertase subtilisin/kexin type 9. Chain: b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pcsk9, narc1. Expressed in: unidentified baculovirus. Expression_system_taxid: 10469. Expression_system_taxid: 10469
Resolution:
2.30Å     R-factor:   0.196     R-free:   0.232
Authors: D.E.Piper,W.G.Romanow,S.T.Thibault,N.P.C.Walker
Key ref:
D.E.Piper et al. (2007). The Crystal Structure of PCSK9: A Regulator of Plasma LDL-Cholesterol. Structure, 15, 545-552. PubMed id: 17502100 DOI: 10.1016/j.str.2007.04.004
Date:
23-Apr-07     Release date:   08-May-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q8NBP7  (PCSK9_HUMAN) -  Proprotein convertase subtilisin/kexin type 9
Seq:
Struc:
 
Seq:
Struc:
692 a.a.
92 a.a.
Protein chain
Pfam   ArchSchema ?
Q8NBP7  (PCSK9_HUMAN) -  Proprotein convertase subtilisin/kexin type 9
Seq:
Struc:
 
Seq:
Struc:
692 a.a.
489 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     serine-type endopeptidase activity     1 term  

 

 
DOI no: 10.1016/j.str.2007.04.004 Structure 15:545-552 (2007)
PubMed id: 17502100  
 
 
The Crystal Structure of PCSK9: A Regulator of Plasma LDL-Cholesterol.
D.E.Piper, S.Jackson, Q.Liu, W.G.Romanow, S.Shetterly, S.T.Thibault, B.Shan, N.P.Walker.
 
  ABSTRACT  
 
Proprotein convertase subtilisin kexin type 9 (PCSK9) has been shown to be involved in the regulation of extracellular levels of the low-density lipoprotien receptor (LDLR). Although PCSK9 is a subtilase, it has not been shown to degrade the LDLR, and its LDLR-lowering mechanism remains uncertain. Here we report the crystal structure of human PCSK9 at 2.3 A resolution. PCSK9 has subtilisin-like pro- and catalytic domains, and the stable interaction between these domains prevents access to PCSK9's catalytic site. The C-terminal domain of PCSK9 has a novel protein fold and may mediate protein-protein interactions. The structure of PCSK9 provides insight into its biochemical characteristics and biological function.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Overall Structure of the PCSK9 Protein
Ribbons diagram of the structure with the prodomain in magenta, the catalytic domain in wheat, and the V domain in blue. Thr61 marks the first observed residue, and Gln152 marks the C terminus of the prodomain. Ser153 marks the N terminus of the catalytic domain.
Figure 2.
Figure 2. The Prodomain Inhibitory Peptide Binds in the Catalytic Site
(A) Stereo view of the catalytic site with 2F[o] − F[c] electron density contoured at 1 σ. P1 residue Gln152 and P3 residue Phe150 are labeled. His226 and Ser386 of the catalytic triad are also shown.
(B) The N-terminal extension interacts with the core β sheet and inhibitory peptide. The first ordered residue in the subtilisin prodomain corresponds with PCSK9 amino acid residue Pro75.
 
  The above figures are reprinted by permission from Cell Press: Structure (2007, 15, 545-552) copyright 2007.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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.  
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.  
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.  
19001363 M.J.Bottomley, A.Cirillo, L.Orsatti, L.Ruggeri, T.S.Fisher, J.C.Santoro, R.T.Cummings, R.M.Cubbon, P.Lo Surdo, A.Calzetta, A.Noto, J.Baysarowich, M.Mattu, F.Talamo, R.De Francesco, C.P.Sparrow, A.Sitlani, and A.Carfí (2009).
Structural and Biochemical Characterization of the Wild Type PCSK9-EGF(AB) Complex and Natural Familial Hypercholesterolemia Mutants.
  J Biol Chem, 284, 1313-1323.
PDB codes: 2w2m 2w2n 2w2o 2w2p 2w2q
19063703 N.G.Seidah (2009).
PCSK9 as a therapeutic target of dyslipidemia.
  Expert Opin Ther Targets, 13, 19-28.  
18375913 A.S.Peterson, L.G.Fong, and S.G.Young (2008).
PCSK9 function and physiology.
  J Lipid Res, 49, 1152-1156.  
18197702 D.Fan, P.G.Yancey, S.Qiu, L.Ding, E.J.Weeber, M.F.Linton, and S.Fazio (2008).
Self-association of human PCSK9 correlates with its LDLR-degrading activity.
  Biochemistry, 47, 1631-1639.  
18266662 J.Cameron, O.L.Holla, J.K.Laerdahl, M.A.Kulseth, T.Ranheim, T.Rognes, K.E.Berge, and T.P.Leren (2008).
Characterization of novel mutations in the catalytic domain of the PCSK9 gene.
  J Intern Med, 263, 420-431.  
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.  
18052825 R.J.Schmidt, Y.Zhang, Y.Zhao, Y.W.Qian, H.Wang, A.Lin, M.E.Ehsani, X.Yu, G.Wang, J.Singh, E.W.Su, S.Li, R.J.Konrad, and G.Cao (2008).
A novel splicing variant of proprotein convertase subtilisin/kexin type 9.
  DNA Cell Biol, 27, 183-189.  
18388699 S.Calandra, and P.Tarugi (2008).
Genetics and molecular biology: proprotein convertase subtilisin/kexin type 9 and LDL receptor--an intriguing story.
  Curr Opin Lipidol, 19, 208-211.  
18331356 S.D.Roosendaal, J.Kerver, M.Schipper, K.W.Rodenburg, and D.J.Van der Horst (2008).
The complex of the insect LDL receptor homolog, lipophorin receptor, LpR, and its lipoprotein ligand does not dissociate under endosomal conditions.
  FEBS J, 275, 1751-1766.  
18245819 S.Kourimate, C.Le May, C.Langhi, A.L.Jarnoux, K.Ouguerram, Y.Zaïr, P.Nguyen, M.Krempf, B.Cariou, and P.Costet (2008).
Dual mechanisms for the fibrate-mediated repression of proprotein convertase subtilisin/kexin type 9.
  J Biol Chem, 283, 9666-9673.  
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.  
17870468 S.C.Blacklow (2007).
Versatility in ligand recognition by LDL receptor family proteins: advances and frontiers.
  Curr Opin Struct Biol, 17, 419-426.  
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.