Program for Structural Biology and Drug Discovery, Van Andel Research Institute, 333 Bostwick Avenue North East, Grand Rapids, Michigan 49503, USA.
Nature. 2013 Aug 22;500(7463):486-9. doi: 10.1038/nature12327. Epub 2013 Jul 14.
Folate receptors (FRα, FRβ and FRγ) are cysteine-rich cell-surface glycoproteins that bind folate with high affinity to mediate cellular uptake of folate. Although expressed at very low levels in most tissues, folate receptors, especially FRα, are expressed at high levels in numerous cancers to meet the folate demand of rapidly dividing cells under low folate conditions. The folate dependency of many tumours has been therapeutically and diagnostically exploited by administration of anti-FRα antibodies, high-affinity antifolates, folate-based imaging agents and folate-conjugated drugs and toxins. To understand how folate binds its receptors, we determined the crystal structure of human FRα in complex with folic acid at 2.8 Å resolution. FRα has a globular structure stabilized by eight disulphide bonds and contains a deep open folate-binding pocket comprised of residues that are conserved in all receptor subtypes. The folate pteroate moiety is buried inside the receptor, whereas its glutamate moiety is solvent-exposed and sticks out of the pocket entrance, allowing it to be conjugated to drugs without adversely affecting FRα binding. The extensive interactions between the receptor and ligand readily explain the high folate-binding affinity of folate receptors and provide a template for designing more specific drugs targeting the folate receptor system.
叶酸受体（FRα、FRβ 和 FRγ）是富含半胱氨酸的细胞表面糖蛋白，能与叶酸高亲和力结合，介导叶酸进入细胞。尽管在大多数组织中表达水平很低，但叶酸受体，尤其是 FRα，在许多癌症中高表达，以满足低叶酸条件下快速分裂细胞对叶酸的需求。通过给予抗 FRα 抗体、高亲和力抗叶酸、叶酸基成像剂和叶酸偶联药物和毒素，利用肿瘤对叶酸的依赖性进行了治疗和诊断。为了了解叶酸如何与其受体结合，我们以 2.8Å 的分辨率确定了人 FRα 与叶酸复合物的晶体结构。FRα 具有由八个二硫键稳定的球形结构，包含一个深的开放叶酸结合口袋，由所有受体亚型都保守的残基组成。叶酸蝶酰基部分埋在受体内部，而其谷氨酸部分暴露在溶剂中并伸出口袋入口，使其能够与药物结合而不影响 FRα 的结合。受体和配体之间的广泛相互作用很好地解释了叶酸受体的高叶酸结合亲和力，并为设计更针对叶酸受体系统的特异性药物提供了模板。
