Molecular modeling of LDLR aids interpretation of genomic variants

In this study, we integrated data from the literature and related cellular receptors to develop high-resolution mode ls of full-length LDLR at extracellular conditions and use them to predict which VUS alter LDL binding. We believe that the functional effects of LDLR variants can be resolved using a combination of structural bioinformatics and functional assays, leading to a better correlation with clinical presen tation. We have completed modeling of LDLR in two major physiologic conditions, generating detailed hypotheses for how each of the 1007 reported protein variants may affect function.Key messages• Hundreds of variants are observed in the LDLR, but most lack interpretation.• Molecular modeling is aided by biochemical knowledge.• We generated context-specific 3D protein models of LDLR.• Our models allowed mechanistic interpretation of many variants.• We interpreted both rare and common genomic variants in their physiologic context.• Effects of genomic variants are often context-specific.
Source: Journal of Molecular Medicine - Category: Molecular Biology Source Type: research