4NMX

PCSK9(deltaCRD) in complex with phage-derived inhibitory peptide 2-8

Summary for 4NMX

• Entry DOI: 10.2210/pdb4nmx/pdb
• Descriptor: Proprotein convertase subtilisin/kexin type 9, peptide 2-8, ... (4 entities in total)
• Functional Keywords: subtlisin, receptor degradation, ldl receptor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: Q8NBP7 Q8NBP7
• Total number of polymer chains: 3
• Total formula weight: 48542.43

Authors

Eigenbrot, C.,Shia, S. (deposition date: 2013-11-15, release date: 2013-12-04, Last modification date: 2024-10-09)

Primary citation

Zhang, Y.,Eigenbrot, C.,Zhou, L.,Shia, S.,Li, W.,Quan, C.,Tom, J.,Moran, P.,Di Lello, P.,Skelton, N.J.,Kong-Beltran, M.,Peterson, A.,Kirchhofer, D.
Identification of a Small Peptide That Inhibits PCSK9 Protein Binding to the Low Density Lipoprotein Receptor.
J.Biol.Chem., 289:942-955, 2014

PubMed Abstract: PCSK9 (proprotein convertase subtilisin/kexin type 9) is a negative regulator of the hepatic LDL receptor, and clinical studies with PCSK9-inhibiting antibodies have demonstrated strong LDL-c-lowering effects. Here we screened phage-displayed peptide libraries and identified the 13-amino acid linear peptide Pep2-8 as the smallest PCSK9 inhibitor with a clearly defined mechanism of inhibition that has been described. Pep2-8 bound to PCSK9 with a KD of 0.7 μm but did not bind to other proprotein convertases. It fully restored LDL receptor surface levels and LDL particle uptake in PCSK9-treated HepG2 cells. The crystal structure of Pep2-8 bound to C-terminally truncated PCSK9 at 1.85 Å resolution showed that the peptide adopted a strand-turn-helix conformation, which is remarkably similar to its solution structure determined by NMR. Consistent with the functional binding site identified by an Ala scan of PCSK9, the structural Pep2-8 contact region of about 400 Å(2) largely overlapped with that contacted by the EGF(A) domain of the LDL receptor, suggesting a competitive inhibition mechanism. Consistent with this, Pep2-8 inhibited LDL receptor and EGF(A) domain binding to PCSK9 with IC50 values of 0.8 and 0.4 μm, respectively. Remarkably, Pep2-8 mimicked secondary structural elements of the EGF(A) domain that interact with PCSK9, notably the β-strand and a discontinuous short α-helix, and it engaged in the same β-sheet hydrogen bonds as EGF(A) does. Although Pep2-8 itself may not be amenable to therapeutic applications, this study demonstrates the feasibility of developing peptidic inhibitors to functionally relevant sites on PCSK9.

PubMed: 24225950
DOI: 10.1074/jbc.M113.514067

Experimental method

X-RAY DIFFRACTION (1.85 Å)