Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford, Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
Institute of Natural Medicine, University of Toyama, Toyama, Japan.
Proteins. 2023 Nov;91(11):1510-1524. doi: 10.1002/prot.26541. Epub 2023 Jul 14.
The hypoxia-inducible factor (HIF) prolyl-hydroxylases (human PHD1-3) catalyze prolyl hydroxylation in oxygen-dependent degradation (ODD) domains of HIFα isoforms, modifications that signal for HIFα proteasomal degradation in an oxygen-dependent manner. PHD inhibitors are used for treatment of anemia in kidney disease. Increased erythropoietin (EPO) in patients with familial/idiopathic erythrocytosis and pulmonary hypertension is associated with mutations in EGLN1 (PHD2) and EPAS1 (HIF2α); a drug inhibiting HIF2α activity is used for clear cell renal cell carcinoma (ccRCC) treatment. We report crystal structures of PHD2 complexed with the C-terminal HIF2α-ODD in the presence of its 2-oxoglutarate cosubstrate or N-oxalylglycine inhibitor. Combined with the reported PHD2.HIFα-ODD structures and biochemical studies, the results inform on the different PHD.HIFα-ODD binding modes and the potential effects of clinically observed mutations in HIFα and PHD2 genes. They may help enable new therapeutic avenues, including PHD isoform-selective inhibitors and sequestration of HIF2α by the PHDs for ccRCC treatment.
缺氧诱导因子 (HIF) 脯氨酰羟化酶（人 PHD1-3）在氧依赖性降解（ODD）结构域中催化 HIFα 同工型的脯氨酰羟化，这些修饰以氧依赖性方式发出 HIFα 蛋白酶体降解的信号。PHD 抑制剂用于治疗肾病贫血。家族性/特发性红细胞增多症和肺动脉高压患者的红细胞生成素 (EPO) 增加与 EGLN1（PHD2）和 EPAS1（HIF2α）的突变有关；一种抑制 HIF2α 活性的药物用于治疗透明细胞肾细胞癌（ccRCC）。我们报告了 PHD2 与 C 末端 HIF2α-ODD 复合物的晶体结构，其中存在其 2-氧戊二酸共底物或 N-草酰甘氨酸抑制剂。结合报道的 PHD2.HIFα-ODD 结构和生化研究，结果说明了不同的 PHD.HIFα-ODD 结合模式以及 HIFα 和 PHD2 基因中临床观察到的突变的潜在影响。它们可能有助于开辟新的治疗途径，包括 PHD 同工型选择性抑制剂和 PHD 对 ccRCC 治疗的 HIF2α 隔离。
