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. 2023 May 1;148(2):144–158. doi: 10.1161/CIRCULATIONAHA.122.063372

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© 2023 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc.

This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.

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Figure 3. — MK-0616-PCSK9 (proprotein convertase subtilisin/kexin type 9) complex. A, Interaction of PCSK9 catalytic domain and prodomain with the LDLR epidermal growth factor and β-propeller domains, respectively, from PDB ID: 3P5B.²¹ B, Modeling MK-0616 from related crystal structures (PDB IDs: 6XID, 6XIE, 75SG, and 75SH)^18,20 suggests MK-0616 (deep teal) interacts with a flat surface on the PCSK9 catalytic domain (pink surface), interrupting the interaction with the EGF(A) domain (transparent yellow) of LDLR. Compound 35 (PDB ID: 7S5H), a closely related analog of Compound 44,^18,20 is shown in white sticks, overlaid with MK-0616 to illustrate the binding site similarity. C, MK-0616 and Compound 35^18,20 can form key hydrogen bonds with T377, F379, and S381 of PCSK9-Cat domain. Cpd 35 indicates Compound 35; EGF, epidermal growth factor; LDLR-EGF, LDL receptor-EGF; PCSK9-Cat, PCSK9-catalytic doman; PCSK9-CTD, PCSK9-C-terminal domain; Phe 379, phenylalanine 379; Ser 381, serine 381; and Thr 377, threonine 377.