Kim Ngoc-Thanh, Do Doan-Loi, Nguyen Mai-Ngoc Thi, Le Hong-An, Le Thanh-Tung, Truong Thanh-Huong
Department of Cardiology, Hanoi Medical University, Hanoi, Vietnam.
Vietnam National Heart Institute, Bach Mai Hospital, Hanoi, Vietnam.
Bioinform Biol Insights. 2024 Nov 28;18:11779322241301267. doi: 10.1177/11779322241301267. eCollection 2024.
Atherosclerotic cardiovascular diseases (CVDs) are closely linked to factors such as familial hypercholesterolemia (FH), often caused by mutations in low-density lipoprotein receptor () and apolipoprotein B (). Through a comprehensive bioinformatic analysis, we identified novel and mutations and their cardiovascular disease (CVD) implications, focusing on unique variants in the Vietnamese population. We used homology modeling to predict protein structures; in addition, through protein-protein molecular docking, we assessed how these mutations affect binding affinities. We identified 10 novel binding residues exclusive to the wild-type and precursor LDLR isoforms, including ASP-47, GLY-48, and GLU-51. Analyses of 154 complexes revealed 5 isoforms with low binding affinities and notable hydrogen-bonding interactions-APOB (Arg3527Trp)-LDLR (Cys318Arg), APOB (His3583Leu)-LDLR (Cys104Tyr), APOB wild-LDLR (Glu228Lys), APOB (Phe2469Cys)-LDLR (Glu288Lys), and APOB wild-LDLR (Ser130Ter). These results suggest strong and potentially detrimental interactions among these proteins. Furthermore, they highlight the molecular mechanisms underlying CVD development, reveal potential therapeutic targets, enhance our understanding of genetic variations, and could guide FH research.
动脉粥样硬化性心血管疾病（CVD）与家族性高胆固醇血症（FH）等因素密切相关，FH通常由低密度脂蛋白受体（）和载脂蛋白B（）的突变引起。通过全面的生物信息学分析，我们确定了新的和突变及其对心血管疾病（CVD）的影响，重点关注越南人群中的独特变异。我们使用同源建模来预测蛋白质结构；此外，通过蛋白质-蛋白质分子对接，我们评估了这些突变如何影响结合亲和力。我们确定了10个野生型和前体LDLR异构体特有的新结合残基，包括ASP-47、GLY-48和GLU-51。对154个复合物的分析揭示了5种具有低结合亲和力和显著氢键相互作用的异构体——APOB（Arg3527Trp）-LDLR（Cys318Arg）、APOB（His3583Leu）-LDLR（Cys104Tyr）、APOB野生型-LDLR（Glu228Lys）、APOB（Phe2469Cys）-LDLR（Glu288Lys）和APOB野生型-LDLR（Ser130Ter）。这些结果表明这些蛋白质之间存在强烈且可能有害的相互作用。此外，它们突出了CVD发展的分子机制，揭示了潜在的治疗靶点，增强了我们对基因变异的理解，并可为FH研究提供指导。
