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首页> 外文期刊>Biochemistry >Engineering a 'Steric doorstop' in rhodopsin: Converting an inverse agonist to an agonist
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Engineering a 'Steric doorstop' in rhodopsin: Converting an inverse agonist to an agonist

机译：在视紫红质中设计“立体门挡”：将反向激动剂转换为激动剂

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摘要

The crystal structures of rhodopsin depict the inactive conformation of rhodopsin in the dark. The 11-cis retinoid chromophore, the inverse agonist holding rhodopsin inactive, is well-resolved. Thr1 18 in helix 3 is the closest amino acid residue next to the 9-methyl group of the chromophore. The 9-methyl group of retinal facilitates the transition from an inactive metarhodopsin I to the active metarhodopsin 11 intermediate. In this study, a site-specific mutation of Thr1 18 to the bulkier Trp was made with the idea to induce an active conformation of the protein.. The data indicate that such a mutation does indeed result in an active protein that depends on the presence of the ligand, specifically the 9-methyl group. As a result of this mutation, 11 -cis retinal has been converted to an agonist. The apoprotein form of this mutant is no more active than the wild-type apoprotein. However, unlike wild-type rhodopsin, the covalent linkage of the ligand can be attacked by hydroxylamine in the dark. The combination of the Thr1 18Trp mutation and the 9-methyl group of the chromophore behaves as a "steric doorstop" holding the protein in an open and active conformation.
机译：视紫红质的晶体结构描述了视紫红质在黑暗中的非活性构象。能使视紫红质失活的反向激动剂11-顺式维甲酸发色团得到了很好的解决。螺旋3中的Thr1 18是最接近发色团9-甲基的氨基酸残基。视网膜的9-甲基有助于从无活性的视紫红质I过渡到有活性的视紫红质11中间体。在这项研究中，将Thr1 18突变为较大的Trp发生了位点特异性诱变，目的是诱导该蛋白的活性构象。数据表明，这种突变确实会导致一种活性蛋白，具体取决于存在配体，特别是9-甲基。由于该突变，11-顺式视网膜已经转化为激动剂。该突变体的载脂蛋白形式不比野生型载脂蛋白更具活性。然而，不同于野生型视紫红质，配体的共价键可在黑暗中被羟胺攻击。 Thr1 18Trp突变和生色团的9-甲基基团的组合表现为“空间门挡”，使蛋白质保持开放和活跃的构象。

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