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首页> 外文期刊>Acta crystallographica.Section D. Biological crystallography >High-resolution structures of mutants of residues that affect access to the ligand-binding cavity of human lipocalin-type prostaglandin D synthase
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High-resolution structures of mutants of residues that affect access to the ligand-binding cavity of human lipocalin-type prostaglandin D synthase

机译：高分辨率结构突变体的残留物影响配体结合腔人类lipocalin-type前列腺素D合酶

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摘要

Lipocalin-type prostaglandin D synthase (L-PGDS) catalyzes the isomerization of the 9,11-endoperoxide group of PGH(2) (prostaglandin H-2) to produce PGD(2) (prostaglandin D-2) with 9-hydroxy and 11-keto groups. The product of the reaction, PGD(2), is the precursor of several metabolites involved in many regulatory events. L-PGDS, the first member of the important lipocalin family to be recognized as an enzyme, is also able to bind and transport small hydrophobic molecules and was formerly known as beta-trace protein, the second most abundant protein in human cerebrospinal fluid. Previous structural work on the mouse and human proteins has focused on the identification of the amino acids responsible and the proposal of a mechanism for catalysis. In this paper, the X-ray structures of the apo and holo forms (bound to PEG) of the C65A mutant of human L-PGDS at 1.40 angstrom resolution and of the double mutant C65A/K59A at 1.60 angstrom resolution are reported. The apo forms of the double mutants C65A/W54F and C65A/W112F and the triple mutant C65A/W54F/W112F have also been studied. Mutation of the lysine residue does not seem to affect the binding of PEG to the ligand-binding cavity, and mutation of a single or both tryptophans appears to have the same effect on the position of these two aromatic residues at the entrance to the cavity. A solvent molecule has also been identified in an invariant position in the cavity of virtually all of the molecules present in the nine asymmetric units of the crystals that have been examined. Taken together, these observations indicate that the residues that have been mutated indeed appear to play a role in the entrance-exit process of the substrate and/or other ligands into/out of the binding cavity of the lipocalin.
机译：Lipocalin-type前列腺素D合酶(L-PGDS)催化异构化的9, 11-endoperoxide群PGH(2)(前列腺素2)生产PGD(2)(前列腺素d2)9-hydroxy和11-keto组。反应,PGD(2)数的前兆代谢产物参与许多监管事件。L-PGDS,第一个重要的成员lipocalin家庭被认为是一种酶,也能够绑定和运输小疏水性分子,原名beta-trace蛋白质,第二个最丰富的在人类的脑脊液蛋白。结构在老鼠和人类的蛋白质一直专注于氨基酸的识别酸负责和机制的建议催化。人群的结构和整体形式(绑定挂钩)C65A突变的人类L-PGDS 1.40埃分辨率和双突变体C65A / K59A 1.60埃分辨率报道。C65A / W54F和C65A / W112F三突变体C65A / W54F W112F也被研究过。的赖氨酸残留物似乎并没有影响绑定挂钩的配体结合腔出现突变的一个或两个色氨酸对这个职位有相同的影响两个芳香残留的入口处腔。在空腔中标识一个不变的位置存在于几乎所有的分子九不对称单位的晶体被检查。表明突变的残留物事实上entrance-exit似乎发挥了作用底物和/或其他配体的过程进/出绑定lipocalin腔。

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