Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 24, Issue 10, Pages 848-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.3453
Keywords
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Funding
- Office of Science, Office of Basic Energy Sciences (BES) of the US Department of Energy (DOE) [DE-AC02-05CH11231, DE-AC02-06CH11357]
- NIH, NIGMS
- HHMI
- DOE Office of Biological and Environmental Research
- NIH, NIGMS [P41GM103393]
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [S10OD021832] Funding Source: NIH RePORTER
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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.
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