CRYSTAL-STRUCTURES OF CELLULAR RETINOIC ACID-BINDING PROTEIN-I AND PROTEIN-II IN COMPLEX WITH ALL-TRANS-RETINOIC ACID AND A SYNTHETIC RETINOID
CRYSTAL-STRUCTURES OF CELLULAR RETINOIC ACID-BINDING PROTEIN-I AND PROTEIN-II IN COMPLEX WITH ALL-TRANS-RETINOIC ACID AND A SYNTHETIC RETINOID
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DOI：
10.1016/s0969-2126(94)00125-1
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发表时间：
1994-12-15
期刊：
影响因子：
5.7
通讯作者：
JONES, TA
中科院分区：
文献类型：
--
作者：
KLEYWEGT, GJ;BERGFORS, T;JONES, TA
背景：维甲酸（RA）在多种细胞活动中起着重要作用。细胞RA结合蛋白（CRABP）被认为是通过调节核RA受体可用的RA量来起作用。CRABP和细胞视黄醇结合蛋白（CRBP）共享封装其配体的两个正交β-折叠的独特折叠。有人认为，三个残基是决定CRBP和CRABP对生理配体高度特异性的主要因素。结果：牛/鼠CRABP I和人CRABP II与其天然配体全反式RA形成复合物。人CRABP II也已与合成类维生素A“化合物19”复合结晶。它们的结构已被确定，并在2.9埃，1.8埃和2.2埃的分辨率，refined，foreign.Conclusions：维甲酸结合位点在CRABP中观察到的CRBP显着不同。蛋白质的三个并列区域的结构变化产生了一个新的，取代的RA结合位点。配体的羧酸根与预期的三个残基（Arg 132、Tyr 134和Arg 111; CRABP II编号）相互作用。RA配体与β-紫罗兰酮环几乎是天然的，相对于异戊二烯尾部，显示出与顺式构象的显著偏差（-33度）。β-紫罗兰酮环的边缘原子以合适的方向可接近溶剂，以呈现给代谢酶。体积较大的合成类维生素A会引起蛋白质结构的微小构象变化。
Background: Retinoic acid (RA) plays a fundamental role in diverse cellular activities. Cellular RA binding proteins (CRABPs) are thought to act by modulating the amount of RA available to nuclear RA receptors. CRABPs and cellular retinol-binding proteins (CRBPs) share a unique fold of two orthogonal beta-sheets that encapsulate their ligands. It has been suggested that a trio of residues are the prime determinants defining the high specificity of CRBPs and CRABPs for their physiological ligands.Results: Bovine/murine CRABP I and human CRABP II have been crystallized in complex with their natural ligand, all-trans-RA. Human CRABP II has also been crystallized in complex with a synthetic retinoid, 'compound 19'. Their structures have been determined and refined at resolutions of 2.9 Angstrom, 1.8 Angstrom and 2.2 Angstrom, respectively.Conclusions: The retinoid-binding site in CRABPs differs significantly from that observed in CRBP. Structural changes in three juxtaposed areas of the protein create a new, displaced binding site for RA. The carboxylate of the ligand interacts with the expected trio of residues (Arg132, Tyr134 and Arg111; CRABP II numbering). The RA ligand is almost nat with the beta-ionone ring showing a significant deviation (-33 degrees) from a cis conformation relative to the isoprene tail. The edge atoms of the beta-ionone ring are accessible to solvent in a suitable orientation for presentation to metabolizing enzymes. The bulkier synthetic retinoid causes small conformational changes in the protein structure.