Structural Basis of Inhibitor Selectivity in Human Indoleamine 2,3-Dioxygenase 1 and Tryptophan Dioxygenase.
Structural Basis of Inhibitor Selectivity in Human Indoleamine 2,3-Dioxygenase 1 and Tryptophan Dioxygenase.
复制标题
DOI：
10.1021/jacs.9b08871
复制
发表时间：
2019-11
影响因子：
15
通讯作者：
K. Pham;A. Lewis-Ballester;S. Yeh
中科院分区：
文献类型：
--
作者：
K. Pham;A. Lewis-Ballester;S. Yeh
吲哚胺 2,3-双加氧酶 1 (hIDO1) 和色氨酸双加氧酶 (hTDO) 是人类仅有的三种基于血红素的双加氧酶中的两种。它们最近被确定为关键的癌症免疫治疗药物靶点。虽然 hIDO1 与抑制剂复合物的结构已被记录，但迄今为止还没有 hTDO-抑制剂复合物的结构。在这里，我们使用临床试验中的 hIDO1 选择性抑制剂 PF-06840003 (IPD) 作为结构探针来阐明 hIDO1 与 hTDO 的抑制剂选择性。光谱研究表明，IPD 对 hIDO1 的抑制活性比 hTDO 高 400 倍。晶体结构表明，hIDO1 活性位点中 IPD 的结合口袋比 hTDO 中的更加灵活，这为 hIDO1 中 IPD 相对于 hTDO 的优异抑制活性提供了分子解释。除了在活性位点结合的 IPD 之外，在 hIDO1 血红素近侧的抑制位点和 hTDO 中距活性位点约 40 Å 的外部位点中还发现了第二个 IPD 分子。总而言之，这些数据为针对 hIDO1 和/或 hTDO 的单抑制剂和双抑制剂的基于结构的设计提供了新的见解。
Indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan dioxygenase (hTDO) are two of the only three heme-based dioxy-genases in humans. They have recently been identified as key cancer immunotherapeutic drug targets. While structures of hIDO1 in complex with inhibitors have been documented, so far there are no structures of hTDO-inhibitor complexes available. Here we use PF-06840003 (IPD), a hIDO1-selective inhibitor in clinical trials, as a structural probe to elucidate inhibitor-selectivity in hIDO1 versus hTDO. Spectroscopic studies show that IPD exhibits 400-fold higher inhibition activ-ity towards hIDO1 with respect to hTDO. Crystallographic structures reveal that the binding pocket of IPD in the active site in hIDO1 is much more flexible as compared to that in hTDO, which offer a molecular explanation for the superior inhibition activity of IPD in hIDO1 with respect to hTDO. In addition to the IPD bound in the active site, a second IPD molecule was identified in an inhibitory site on the proximal side of the heme in hIDO1 and in an exosite that is ~40 Å away from the active site in hTDO. Taken together the data provide new insights into structure-based design of mono and dual inhibitors targeting hIDO1 and/or hTDO.