Crystal structure of prostate-specific membrane antigen, a tumor marker and peptidase
Crystal structure of prostate-specific membrane antigen, a tumor marker and peptidase
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DOI：
10.1073/pnas.0502101102
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发表时间：
2005-04-26
影响因子：
11.1
通讯作者：
Bjorkman, PJ
中科院分区：
文献类型：
--
作者：
Davis, MI;Bennett, MJ;Bjorkman, PJ
前列腺特异性膜抗原（PSMA）在前列腺癌细胞和非前列腺实体瘤新血管中高度表达，是抗癌成像和治疗药物的靶点。PSMA作为谷氨酸羧肽酶（GCPII）作用于小分子底物，包括叶酸、抗癌药物甲氨蝶呤和神经肽N-乙酰基-L-乙酰基-L-谷氨酸。在这里，我们提出了PSMA胞外域的3.5埃晶体结构，其揭示了与转铁蛋白受体（缺乏蛋白酶活性的铁负载转铁蛋白的受体）具有结构相似性的同二聚体。与转铁蛋白受体不同，PSMA的蛋白酶结构域包含双核锌位点、催化残基和提议的底物结合精氨酸补丁。PSMA结构的阐明结合对接研究和提出的催化机制提供了对抑制剂和天然底物N-乙酰基-L-乙酰基-L-谷氨酸的识别的深入了解。PSMA结构将促进化学治疗剂、癌症成像剂和用于治疗神经障碍的药剂的开发。
Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer cells and nonprostatic solid tumor neovasculature and is a target for anticancer imaging and therapeutic agents. PSMA acts as a glutamate carboxypeptidase (GCPII) on small molecule substrates, including folate, the anticancer drug methotrexate, and the neuropeptide N-acetyl-L-aspartyl-L-glutamate. Here we present the 3.5-angstrom crystal structure of the PSMA ectodomain, which reveals a homodimer with structural similarity to transferrin receptor, a receptor for iron-loaded transferrin that lacks protease activity. Unlike transferrin receptor, the protease domain of PSMA contains a binuclear zinc site, catalytic residues, and a proposed substrate-binding arginine patch. Elucidation of the PSMA structure combined with docking studies and a proposed catalytic mechanism provides insight into the recognition of inhibitors and the natural substrate N-acetyl-L-aspartyl-L-glutamate. The PSMA structure will facilitate development of chemotherapeutics, cancer-imaging agents, and agents for treatment of neurological disorders.