The human CYP2C9 plays a crucial role in the metabolic clearance of a wide range of clinical therapeutics. The *2 allele is a prevalent genetic variation in CYP2C9 that is found in various populations. A marked reduction of catalytic activity toward many important drug substrates has been demonstrated by CYP2C9*2, which represents an amino acid variation at position 144 from arginine to cysteine. The crystal structure of CYP2C9*2 in complex with an antihypertensive drug losartan was solved using X-ray crystallography at 3.1-Å resolution. The Arg144Cys variation in the *2 complex disrupts the hydrogen-bonding interactions that were observed between the side chain of arginine and neighboring residues in the losartan complex of CYP2C9 and the wild-type (WT) ligand-free structure. The conformation of several secondary structural elements is affected, thereby altering the binding and orientation of drug and important amino acid side chains in the distal active site cavity. The new structure revealed distinct interactions of losartan in the compact active site of CYP2C9*2 and differed in occupancy at the other binding sites previously identified in the WT-losartan complex. Furthermore, the binding studies in solution using losartan illustrated lower activity of the CYP2C9*2 compared with the WT. Together, the findings yield valuable insights into the decreased hydroxylation activity of losartan in patients carrying CYP2C9*2 allele and provide a useful framework to investigate the effect of a single-nucleotide polymorphism that leads to altered metabolism of diverse drug substrates.

中文翻译：

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与抗高血压药物氯沙坦复合的细胞色素 P450 2C9*2 的结构：对遗传多态性影响的洞察。

人类 CYP2C9 在广泛的临床治疗药物的代谢清除中起着至关重要的作用。*2 等位基因是 CYP2C9 中普遍存在的遗传变异，可在不同人群中发现。CYP2C9*2 已证明对许多重要药物底物的催化活性显着降低，这代表了 144 位氨基酸从精氨酸到半胱氨酸的变异。CYP2C9*2 与抗高血压药物氯沙坦复合物的晶体结构使用 X 射线晶体学以 3.1 Å 分辨率解析。*2 复合物中的 Arg144Cys 变异破坏了在精氨酸侧链和 CYP2C9 氯沙坦复合物中的相邻残基与野生型 (WT) 无配体结构之间观察到的氢键相互作用。几个二级结构元素的构象受到影响，从而改变药物和重要氨基酸侧链在远端活性位点腔中的结合和方向。新结构揭示了氯沙坦在 CYP2C9*2 紧密活性位点的不同相互作用，并且在先前在 WT-氯沙坦复合物中确定的其他结合位点的占有率不同。此外，使用氯沙坦在溶液中的结合研究表明，与 WT 相比，CYP2C9*2 的活性较低。总之，这些发现对携带 CYP2C9*2 等位基因的患者中氯沙坦的羟基化活性降低提供了有价值的见解，并提供了一个有用的框架来研究单核苷酸多态性导致不同药物底物代谢改变的影响。