5OCA

PCSK9:Fab Complex with Dextran Sulfate

Summary for 5OCA

• Entry DOI: 10.2210/pdb5oca/pdb
• Related PRD ID: PRD_900071
• Descriptor: Proprotein convertase subtilisin/kexin type 9, Fab from LDLR competitive antibody: Heavy chain, Fab from LDLR competitive antibody: Light chain, ... (7 entities in total)
• Functional Keywords: hydrolase, protein fab complex, autocatalytic cleavage, cholesterol metabolism, disease mutation, disulfide bond, glycoprotein, lipid metabolism, phosphoprotein, protease, secreted, serine protease, steroid metabolism, zymogen, hydrolase-immune system complex
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 120341.24

Authors

Thirup, S.S.,Vilstrup, J.P. (deposition date: 2017-06-30, release date: 2017-09-20, Last modification date: 2024-11-06)

Primary citation

Gustafsen, C.,Olsen, D.,Vilstrup, J.,Lund, S.,Reinhardt, A.,Wellner, N.,Larsen, T.,Andersen, C.B.F.,Weyer, K.,Li, J.P.,Seeberger, P.H.,Thirup, S.,Madsen, P.,Glerup, S.
Heparan sulfate proteoglycans present PCSK9 to the LDL receptor.
Nat Commun, 8:503-503, 2017

PubMed Abstract: Coronary artery disease is the main cause of death worldwide and accelerated by increased plasma levels of cholesterol-rich low-density lipoprotein particles (LDL). Circulating PCSK9 contributes to coronary artery disease by inducing lysosomal degradation of the LDL receptor (LDLR) in the liver and thereby reducing LDL clearance. Here, we show that liver heparan sulfate proteoglycans are PCSK9 receptors and essential for PCSK9-induced LDLR degradation. The heparan sulfate-binding site is located in the PCSK9 prodomain and formed by surface-exposed basic residues interacting with trisulfated heparan sulfate disaccharide repeats. Accordingly, heparan sulfate mimetics and monoclonal antibodies directed against the heparan sulfate-binding site are potent PCSK9 inhibitors. We propose that heparan sulfate proteoglycans lining the hepatocyte surface capture PCSK9 and facilitates subsequent PCSK9:LDLR complex formation. Our findings provide new insights into LDL biology and show that targeting PCSK9 using heparan sulfate mimetics is a potential therapeutic strategy in coronary artery disease.PCSK9 interacts with LDL receptor, causing its degradation, and consequently reduces the clearance of LDL. Here, Gustafsen et al. show that PCSK9 interacts with heparan sulfate proteoglycans and this binding favors LDLR degradation. Pharmacological inhibition of this binding can be exploited as therapeutic intervention to lower LDL levels.

PubMed: 28894089
DOI: 10.1038/s41467-017-00568-7

Experimental method

X-RAY DIFFRACTION (2.3 Å)