Phenylsulfamoyl Benzoic Acid Inhibitor of ERAP2 with a Novel Mode of Inhibition.
Phenylsulfamoyl Benzoic Acid Inhibitor of ERAP2 with a Novel Mode of Inhibition.
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具有新型抑制模式的 ERAP2 苯基氨磺酰苯甲酸抑制剂。
DOI：
10.1021/acschembio.2c00093
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发表时间：
2022
影响因子：
4
通讯作者：
Stern,LawrenceJ
中科院分区：
文献类型：
--
作者：
Arya,Richa;Maben,Zachary;Rane,Digamber;Ali,Akbar;Stern,LawrenceJ
ERAP1和ERAP2是内质网锌结合氨基肽酶，在处理多肽以装载到I类主要组织相容性复合体蛋白中起着至关重要的作用。这些酶是癌症和自身免疫性疾病的治疗靶点。由于ERAP1或ERAP2的活性部位残基和结构域结构相似，发现ERAP1或ERAP2的特异性抑制剂一直是具有挑战性的。在这里，我们确定4-methoxy-3-{[2-piperidin-1-yl-4-(trifluoromethyl)苯基]磺酰基)苯甲酸(化合物61)是ERAP2的一种新的抑制剂，并确定了与化合物61结合的ERAP2的晶体结构。化合物61在ERAP2的催化中心附近结合，位于与已知的模拟肽抑制剂不同的位置，并通过非竞争性机制抑制。令人惊讶的是，对于ERAP1，化合物61被发现激活了模型底物水解，类似于之前描述的化合物61的5-三氟甲基区域异构体，称为化合物3。我们表征了控制化合物3和61结合的ERAP1和ERAP2的特异性决定因素。在ERAP1的活性部位，S1‘口袋中的Lys380是化合物3和61结合的关键决定因素。在变构位置，ERAP1与任何一种化合物结合，导致模型底物水解的激活。尽管这两种化合物都不能激活ERAP2底物的水解，但His904突变为丙氨酸显示了一个隐蔽的变构位点，允许化合物3激活。因此，我们已经在ERAP2的活性和变构位置确定了控制两个类似化合物结合的选择性决定因素，这可能被利用来开发更有效和特异的抑制剂。
ERAP1 and ERAP2 are endoplasmic reticulum zinc-binding aminopeptidases that play crucial roles in processing peptides for loading onto class I major histocompatibility complex proteins. These enzymes are therapeutic targets in cancer and autoimmune disorders. The discovery of inhibitors specific to ERAP1 or ERAP2 has been challenging due to the similarity in their active site residues and domain architectures. Here, we identify 4-methoxy-3-{[2-piperidin-1-yl-4-(trifluoromethyl) phenyl] sulfamoyl} benzoic acid (compound61) as a novel inhibitor of ERAP2 and determine the crystal structure of ERAP2 bound to compound61. Compound61binds near the catalytic center of ERAP2, at a distinct site from previously known peptidomimetic inhibitors, and inhibits by an uncompetitive mechanism. Surprisingly, for ERAP1, compound61was found to activate model substrate hydrolysis, similarly to the previously characterized 5-trifluoromethyl regioisomer of compound61, known as compound3.We characterized the specificity determinants of ERAP1 and ERAP2 that control the binding of compounds3and61. At the active site of ERAP1, Lys380 in the S1′ pocket is a key determinant for the binding of both compounds3and61. At the allosteric site, ERAP1 binds either compound, leading to the activation of model substrate hydrolysis. Although ERAP2 substrate hydrolysis is not activated by either compound, the mutation of His904 to alanine reveals a cryptic allosteric site that allows for the activation by compound3. Thus, we have identified selectivity determinants in the active and allosteric sites of ERAP2 that govern the binding of two similar compounds, which potentially could be exploited to develop more potent and specific inhibitors.
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ERAP1 多态性与强直性脊柱炎易感性之间的关联：荟萃分析
影响因子：
3.4
作者：
Y. Lee;G. Song
通讯作者：
G. Song
通过筛选含磷氨基酸和二肽类似物文库，发现人氨肽酶 ERAP1 和 ERAP2 的有效选择性抑制剂。
影响因子：
2.7
作者：
Ewelina Węglarz;S. Vassiliou;A. Mucha
通讯作者：
A. Mucha
DOI：
10.1073/pnas.0500721102
发表时间：
2005-11-22
影响因子：
11.1
作者：
Chang, SC;Momburg, F;Goldberg, AL
通讯作者：
Goldberg, AL
影响因子：
2.8
作者：
Sui L;Guo HC
通讯作者：
Guo HC
影响因子：
7.3
作者：
Liddle, John;Hutchinson, Jonathan P.;Stratikos, Efstratios
通讯作者：
Stratikos, Efstratios