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.

中文翻译：

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在PCSK9上发现一个隐性肽结合位点并设计拮抗剂

前蛋白转化酶枯草杆菌蛋白酶/ kexin 9型（PCSK9）通过促进肝脏LDL受体（LDLRs）的降解来调节血浆LDL胆固醇（LDL-c）的水平。抑制PCSK9与LDLR的EGF（A）域结合的抗体可有效降低LDL-c。但是，难以靶向PCSK9上相对平坦的EGF（A）结合位点阻碍了小分子治疗剂的发现。在这里，我们证明，基于PCSK9 P'螺旋显示构象灵活性的发现，可以将此位点作为目标。结果，与EGF（A）结合位点相邻的PCSK9的空出的N末端凹槽实际上是小肽可及的。在噬菌体展示实验中 EGF（A）模仿肽Pep2-8用作锚定肽，用于连接引向凹槽位点的延伸肽文库。在结构信息的指导下，我们将识别出的沟结合肽进一步工程化为拮抗剂，从而侵蚀了EGF（A）结合位点并抑制了LDLR结合。