4LRH

Crystal structure of human folate receptor alpha in complex with folic acid

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4LRH の概要

• エントリーDOI: 10.2210/pdb4lrh/pdb
• 分子名称: Folate receptor alpha, FOLIC ACID, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• 機能のキーワード: folate receptor-alpha, folic acid, folate binding protein, cysteine-rich glycoprotein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 212748.59

構造登録者

Ke, J.,Chen, C.,Zhou, X.E.,Yi, W.,Brunzelle, J.S.,Li, J.,Young, E.-L.,Xu, H.E.,Melcher, K. (登録日: 2013-07-19, 公開日: 2013-07-31, 最終更新日: 2024-11-27)

主引用文献

Chen, C.,Ke, J.,Zhou, X.E.,Yi, W.,Brunzelle, J.S.,Li, J.,Yong, E.L.,Xu, H.E.,Melcher, K.
Structural basis for molecular recognition of folic acid by folate receptors.
Nature, 500:486-489, 2013

PubMed Abstract: 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.

PubMed: 23851396
DOI: 10.1038/nature12327

実験手法

X-RAY DIFFRACTION (2.8 Å)