Structural Basis of Prolyl Hydroxylase Domain Inhibition by Molidustat.
Structural Basis of Prolyl Hydroxylase Domain Inhibition by Molidustat.
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DOI：
10.1002/cmdc.202100133
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发表时间：
2021-07-06
期刊：
影响因子：
3.4
通讯作者：
Schofield CJ
中科院分区：
文献类型：
--
作者：
Figg WD Jr;McDonough MA;Chowdhury R;Nakashima Y;Zhang Z;Holt-Martyn JP;Krajnc A;Schofield CJ
人类脯氨酸羟基酶(PhDS)是一种对低氧敏感的2-氧戊二酸(2OG)加氧酶，其催化作用是抑制低氧诱导因子靶基因的转录。抑制PHD使贫血/缺血相关疾病得以治疗。PHD抑制剂Molidustat被批准用于治疗肾性贫血；它与其他已批准的/晚期PHD抑制剂的不同之处在于缺乏甘氨酰胺侧链。首次报道了Molidustat和IOX4(一种脑穿透性衍生物)与PHD2络合的晶体结构，揭示了它们连续的三氮唑、吡唑酮和嘧啶/吡啶环如何结合在活性中心上。这些缓蚀剂通过它们的吡唑酮和嘧啶氮以双齿方式结合到活性中心金属上，三氮唑π-π-堆积在20G结合口袋中与Tyr303。将新结构与其他PHD抑制剂复合体进行比较，发现Tyr303、Tyr310和连接β2-β3的移动环的构象不同，它们参与了动态底物结合/产物释放。环结合剂：人PHD2与莫利度坦和相关抑制剂的共晶结构提供了对它们的抑制模式的洞察。莫利度他的吡唑酮-嘧啶环与活性中心的金属离子发生络合作用，其三唑环与Tyr303发生π-π堆积作用。结果表明，包括Tyr303和Tyr310在内的PHD2残基在与铁络合型PHD抑制剂结合时发生了构象变化。
Human prolyl‐hydroxylases (PHDs) are hypoxia‐sensing 2‐oxoglutarate (2OG) oxygenases, catalysis by which suppresses the transcription of hypoxia‐inducible factor target genes. PHD inhibition enables the treatment of anaemia/ischaemia‐related disease. The PHD inhibitor Molidustat is approved for the treatment of renal anaemia; it differs from other approved/late‐stage PHD inhibitors in lacking a glycinamide side chain. The first reported crystal structures of Molidustat and IOX4 (a brain‐penetrating derivative) complexed with PHD2 reveal how their contiguous triazole, pyrazolone and pyrimidine/pyridine rings bind at the active site. The inhibitors bind to the active‐site metal in a bidentate manner through their pyrazolone and pyrimidine nitrogens, with the triazole π‐π‐stacking with Tyr303 in the 2OG binding pocket. Comparison of the new structures with other PHD inhibitor complexes reveals differences in the conformations of Tyr303, Tyr310, and a mobile loop linking β2–β3, which are involved in dynamic substrate binding/product release. Ring binder: Co‐crystal structures of human PHD2 with Molidustat and a related inhibitor provide insight into their mode of inhibition. The pyrazolone‐pyrimidine rings of Molidustat chelate the active‐site metal ion, and its triazole ring makes a π‐π‐stacking interaction with Tyr303. The results reveal altered conformations of PHD2 residues, including Tyr303 and Tyr310 on binding of Fe‐chelating PHD inhibitors.
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影响因子：
3.4
作者：
Beck H;Jeske M;Thede K;Stoll F;Flamme I;Akbaba M;Ergüden JK;Karig G;Keldenich J;Oehme F;Militzer HC;Hartung IV;Thuss U
通讯作者：
Thuss U
使用环肽诱导结晶：脯氨酰羟化酶结构域 2 的案例研究。
影响因子：
4.6
作者：
Chowdhury R;Abboud MI;McAllister TE;Banerji B;Bhushan B;Sorensen JL;Kawamura A;Schofield CJ
通讯作者：
Schofield CJ
DOI：
10.1039/c8cc00387d
发表时间：
2018-03-28
期刊：
Chemical communications (Cambridge, England)
影响因子：
--
作者：
Abboud MI;McAllister TE;Leung IKH;Chowdhury R;Jorgensen C;Domene C;Mecinović J;Lippl K;Hancock RL;Hopkinson RJ;Kawamura A;Claridge TDW;Schofield CJ
通讯作者：
Schofield CJ
影响因子：
8.4
作者：
Yeh, Tzu-Lan;Leissing, Thomas M.;Schofield, Christopher J.
通讯作者：
Schofield, Christopher J.
影响因子：
3.7
作者：
Chan MC;Atasoylu O;Hodson E;Tumber A;Leung IK;Chowdhury R;Gómez-Pérez V;Demetriades M;Rydzik AM;Holt-Martyn J;Tian YM;Bishop T;Claridge TD;Kawamura A;Pugh CW;Ratcliffe PJ;Schofield CJ
通讯作者：
Schofield CJ