Structure of human FIH-1 reveals a unique active site pocket and interaction sites for HIF-1 and von Hippel-Lindau
Structure of human FIH-1 reveals a unique active site pocket and interaction sites for HIF-1 and von Hippel-Lindau
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DOI：
10.1074/jbc.m210385200
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发表时间：
2003-02-28
影响因子：
4.8
通讯作者：
Ryu, SE
中科院分区：
文献类型：
--
作者：
Lee, C;Kim, SJ;Ryu, SE
缺氧诱导因子1（HIF-1）是细胞缺氧反应的主开关，在常氧条件下被HIF-1抑制因子（FIH-1）在保守的天冬酰胺残基上羟基化，通过消除HIF-1与转录辅激活因子的相互作用来抑制HIF-1的转录活性。在这里，我们报告了2.8埃分辨率的人FIH-1的晶体结构。FIH-1的结构核心由一个含有保守的亚铁结合三联体残基的β-桶组成，证实FIH-1是2-酮戊二酸依赖性双加氧酶家族的成员。除了核心结构和三联体残基，FIH-1与其他家族成员有许多结构上的差异，包括N-和C-末端的插入和结构中间的各种缺失。亚铁结合三联体区域高度暴露于溶剂，其连接到突出的凹槽，该凹槽可以结合到HIF-1的羟基化位点附近的螺旋。该结构，这是在一个二聚体状态，也揭示了推定的冯希佩尔-林道结合位点，这是独特的推定的HIF-1结合位点，支持由FIH-1，HIF-1，和冯希佩尔-林道三元复合物的形成。结构中所揭示的活性位点和辅因子结合区的独特环境应允许设计可用于缺血性疾病的选择性药物以促进缺氧反应。
The master switch of cellular hypoxia responses, hypoxia-inducible factor 1 (HIF-1), is hydroxylated by factor inhibiting HIF-1 (FIH-1) at a conserved asparagine residue under normoxia, which suppresses transcriptional activity of HIF-1 by abrogating its interaction with transcription coactivators. Here we report the crystal structure of human FIH-1 at 2.8-Angstrom resolution. The structural core of FIH-1 consists of a jellyroll-like beta-barrel containing the conserved ferrous-binding triad residues, confirming that FIH-1 is a member of the 2-oxoglutarate-dependent dioxygenase family. Except for the core structure and triad residues, FIH-1 has many structural deviations from other family members including N- and C-terminal insertions and various deletions in the middle of the structure. The ferrous-binding triad region is highly exposed to the solvent, which is connected to a prominent groove that may bind to a helix near the hydroxylation site of HIF-1. The structure, which is in a dimeric state, also reveals the putative von Hippel-Lindau-binding site that is distinctive to the putative HIF-1-binding site, supporting the formation of the ternary complex by FIH-1, HIF-1, and von Hippel-Lindau. The unique environment of the active site and cofactor-binding region revealed in the structure should allow design of selective drugs that can be used in ischemic diseases to promote hypoxia responses.