肝细胞核因子4α（HNF4α）是一个多功能的核受体，负责控制肝脏和胰岛细胞的发育和正常功能。它的转录功能包括调节重要的代谢过程，包括胆固醇和脂肪酸代谢，以及葡萄糖感知和控制。HNF4α的各种遗传突变和改变与糖尿病、代谢紊乱和癌症有关。从结构的角度来看，由于晶体学观察到的结构，HNF4α是最全面理解的核受体之一，它的结构显示出相互连接的DNA结合结构域（DBDs）和配体结合结构域（LBDs）。本综述讨论了HNF4α的关键特性，包括其同二聚化方式、与脂肪酸配体的结合、翻译后修饰的重要性以及伪装功能的机制基础。连接HNF4α的DBDs和LBDs的表面创建了一个汇聚区，允许来自任何一个结构域的信号影响远处的结构域。HNF4α-DNA复合物是核受体如何利用各个结构域进行特定功能的一个典型示例，同时也整合了这些结构域，创建了统一的高阶体系结构，从而实现信号响应功能。Copyright © 2023 Rastinejad.

Hepatocyte nuclear factor 4 alpha (HNF4α) is a multi-faceted nuclear receptor responsible for governing the development and proper functioning of liver and pancreatic islet cells. Its transcriptional functions encompass the regulation of vital metabolic processes including cholesterol and fatty acid metabolism, and glucose sensing and control. Various genetic mutations and alterations in HNF4α are associated with diabetes, metabolic disorders, and cancers. From a structural perspective, HNF4α is one of the most comprehensively understood nuclear receptors due to its crystallographically observed architecture revealing interconnected DNA binding domains (DBDs) and ligand binding domains (LBDs). This review discusses key properties of HNF4α, including its mode of homodimerization, its binding to fatty acid ligands, the importance of post-translational modifications, and the mechanistic basis for allosteric functions. The surfaces linking HNF4α's DBDs and LBDs create a convergence zone that allows signals originating from any one domain to influence distant domains. The HNF4α-DNA complex serves as a prime illustration of how nuclear receptors utilize individual domains for specific functions, while also integrating these domains to create cohesive higher-order architectures that allow signal responsive functions.Copyright © 2023 Rastinejad.