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Figure 3.
Mutations in PCSK9 and LDLR. (A) The gain-of-function
mutation Asp-374–Tyr in PCSK9 increases binding to LDLR.
Asp-374 in PCSK9 modeled as tyrosine (gray) is in position to
hydrogen bond to His-306 of LDLR. (B) The FH mutation
His-306–Tyr in LDLR. His-306 in LDLR modeled as tyrosine
(gray) is in position to hydrogen bond to Asp-374 of PCSK9. (C)
Model for full-length LDLR-ECD bound to PCSK9. The EGF-A domain
(blue) of the LDLR-ECD (cyan) at acidic pH and the PCKSK9:EGF-A
complex were superimposed. PCSK9 (prodomain, magenta;
subtilisin-like catalytic domain, green; C-terminal domain,
brown) binds on the outside surface of LDLR and would not
interfere with the interaction of ligand binding modules R4 and
R5 with the β-propeller domain.
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