Mpakali Anastasia, Georgiadis Dimitris, Stratikos Efstratios, Giastas Petros
National Centre for Scientific Research Demokritos, Agia Paraskevi, Athens 15341, Greece.
Laboratory of Organic Chemistry, Chemistry Department, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, Athens 15771, Greece.
ACS Med Chem Lett. 2022 Jan 13;13(2):218-224. doi: 10.1021/acsmedchemlett.1c00582. eCollection 2022 Feb 10.
Endoplasmic reticulum aminopeptidase 2 (ERAP2) is an intracellular enzyme involved in the processing of antigenic peptides intended for presentation by major histocompatibility complex class I (MHCI) molecules. Because of its role in regulating immune responses, ERAP2 is an emerging pharmacological target. Phosphinic pseudopeptides are potent transition-state analogue inhibitors of ERAP2. Previous structure-activity studies have revealed a complex but ambiguous relationship between the occupation of putative specificity pockets and the inhibitor efficacy. To address these problems, we solved crystal structures of ERAP2 in complex with two phosphinic pseudotripeptide inhibitors. Both compounds are found in the catalytic site in a canonical orientation for transition-state analogues and utilize the S1 and S2' pockets in a similar fashion. Strikingly, their P1' side chains exhibit different orientations and make interactions with distinct shallow pockets near the ERAP2 active site. These structures suggest that S1' pocket usage in ERAP2 may be inhibitor-dependent and constitute useful starting templates for the further optimization of this class of compounds.
内质网氨肽酶2（ERAP2）是一种细胞内酶，参与主要组织相容性复合体I类（MHCI）分子呈递的抗原肽的加工过程。由于其在调节免疫反应中的作用，ERAP2正成为一个新兴的药理学靶点。次膦基假肽是ERAP2的强效过渡态类似物抑制剂。先前的构效关系研究揭示了假定特异性口袋的占据与抑制剂效力之间复杂但不明确的关系。为了解决这些问题，我们解析了ERAP2与两种次膦基假三肽抑制剂复合物的晶体结构。两种化合物均以过渡态类似物的典型取向存在于催化位点，并以类似方式利用S1和S2'口袋。引人注目的是，它们的P1'侧链呈现不同取向，并与ERAP2活性位点附近不同的浅口袋相互作用。这些结构表明，ERAP2中S1'口袋的使用可能依赖于抑制剂，并构成了进一步优化这类化合物的有用起始模板。
