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首页> 外文期刊>Biochemistry >Structural and Thermodynamic Consequences of 1-(4-Chlorophenyl)imidazole Binding to Cytochrome P450 2B4
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Structural and Thermodynamic Consequences of 1-(4-Chlorophenyl)imidazole Binding to Cytochrome P450 2B4

机译：1-（4-氯苯基）咪唑与细胞色素P450 2B4结合的结构和热力学后果

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The crystal structure of P450 2B4 bound with 1-(4-chlorophenyl)imidazole(1-CPI)has been determined to delineate the structural basis for the observed differences in binding affinity and thermodynamics relative to 4-(4-chlorophenyl)imidazole(4-CPI).Compared with the previously reported 4-CPI complex,there is a shift in the 1-CPI complex of the protein backbone in helices F and I,repositioning the side chains of Phe-206,Phe-297,and Glu-301,and leading to significant reshaping of the active site.Phe-206 and Phe-297 exchange positions,with Phe-206 becoming a ligand-contact residue,while Glu-301,rather than hydrogen bonding to the ligand,flips away from the active site and interacts with His-172.As a result the active site volume expands from 200 A3 in the 4-CPI complex to 280 A3 in the 1-CPI complex.Based on the two structures,it was predicted that a Phe-206->Ala substitution would alter 1-CPI but not 4-CPI binding.Isothermal titration calorimetry experiments indicated that this substitution had no effect on the thermodynamic signature of 4-CPI binding to 2B4.In contrast,relative to wild-type 1-CPI binding to F206A showed significantly less favorable entropy but more favorable enthalpy.This result is consistent with loss of the aromatic side chain and possible ordering of water molecules,now able to interact with Glu-301 and exposed residues in the I-helix.Hence,thermodynamic measurements support the active site rearrangement observed in the crystal structure of the 1-CPI complex and illustrate the malleability of the active site with the fine-tuning of residue orientations and thermodynamic signatures.
机译：已确定与1-（4-氯苯基）咪唑（1-CPI）结合的P450 2B4的晶体结构为描述相对于4-（4-氯苯基）咪唑（4）的结合亲和力和热力学差异提供了结构基础。 -CPI）。与先前报道的4-CPI复合物相比，螺旋F和I中蛋白质骨架的1-CPI复合物发生了变化，从而重新排列了Phe-206，Phe-297和Glu- Phe-206和Phe-297交换位置，使Phe-206成为配体接触残基，而Glu-301而不是氢键合到配体上，从而从301转移，并导致活性位点显着重塑。活性位点并与His-172相互作用。结果，活性位点体积从4-CPI复合物中的200 A3扩展到1-CPI复合物中的280 A3。基于这两种结构，可以预测Phe-206 -> Ala取代会改变1-CPI结合但不会改变4-CPI结合。等温滴定热法实验表明，该取代基相对于野生型1-CPI与F206A的结合，熵对F206A的热力学特征没有影响。相反，与野生型1-CPI与F206A的结合表现出显着降低的熵但更有利的焓。现在可以与Glu-301和I螺旋中的暴露残基相互作用的水分子链和可能的有序排列。因此，热力学测量结果支持了在1-CPI配合物晶体结构中观察到的活性位点重排，并说明了其可塑性。对活性位点的残基方向和热力学特征进行微调。

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