5VLK

Short PCSK9 delta-P' complex with shrunken peptide bearing homo-Arginine

Summary for 5VLK

• Entry DOI: 10.2210/pdb5vlk/pdb
• Related: 5VL7 5VLA 5VLH 5VLL 5VLP
• Descriptor: Proprotein convertase subtilisin/kexin type 9, ACE-THR-VAL-PHE-THR-SER-TRP-GLU-GLU-TYR-LEU-ASP-TRP-VAL-NH2 peptide, ACE-TRP-ASN-LEU-VAL-HRG-ILE-GLY-LEU-LEU peptide, ... (5 entities in total)
• Functional Keywords: proprotein convertase, subtilisin, hydrolase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 52803.65

Authors

Eigenbrot, C.,Ultsch, M. (deposition date: 2017-04-25, release date: 2017-08-16, Last modification date: 2023-11-15)

Primary citation

Zhang, Y.,Ultsch, M.,Skelton, N.J.,Burdick, D.J.,Beresini, M.H.,Li, W.,Kong-Beltran, M.,Peterson, A.,Quinn, J.,Chiu, C.,Wu, Y.,Shia, S.,Moran, P.,Di Lello, P.,Eigenbrot, C.,Kirchhofer, D.
Discovery of a cryptic peptide-binding site on PCSK9 and design of antagonists.
Nat. Struct. Mol. Biol., 24:848-856, 2017

PubMed Abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma LDL cholesterol (LDL-c) levels by promoting the degradation of liver LDL receptors (LDLRs). Antibodies that inhibit PCSK9 binding to the EGF(A) domain of the LDLR are effective in lowering LDL-c. However, the discovery of small-molecule therapeutics is hampered by difficulty in targeting the relatively flat EGF(A)-binding site on PCSK9. Here we demonstrate that it is possible to target this site, based on the finding that the PCSK9 P' helix displays conformational flexibility. As a consequence, the vacated N-terminal groove of PCSK9, which is adjacent to the EGF(A)-binding site, is in fact accessible to small peptides. In phage-display experiments, the EGF(A)-mimicking peptide Pep2-8 was used as an anchor peptide for the attachment of an extension peptide library directed toward the groove site. Guided by structural information, we further engineered the identified groove-binding peptides into antagonists, which encroach on the EGF(A)-binding site and inhibit LDLR binding.

PubMed: 28825733
DOI: 10.1038/nsmb.3453

Experimental method

X-RAY DIFFRACTION (2.2 Å)