抗伤害感受药SBFI-26在两个不同的位置与Anandamide转运蛋白FABP5和FABP7结合,Biochemistry

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抗伤害感受药SBFI-26在两个不同的位置与Anandamide转运蛋白FABP5和FABP7结合
Biochemistry ( IF 2.9 ) Pub Date : 2017-06-28 00:00:00 , DOI: 10.1021/acs.biochem.7b00194
Hao-Chi Hsu ₁ , Simon Tong ₂ , Yuchen Zhou ₃ , Matthew W. Elmes ₄ , Su Yan ₂ , Martin Kaczocha _{4,

5} , Dale G. Deutsch _{4,

6} , Robert C. Rizzo _{3,

6,

7} , Iwao Ojima _{2,

6} , Huilin Li _{1,

6}

Affiliation

人FABP5和FABP7是细胞内大麻素转运蛋白。SBFI-26是一种α-truxillicacid 1-萘基单酯，可竞争性抑制FABP5和FABP7的活性，并在小鼠中产生镇痛和抗炎作用。SBFI-26的合成会产生几种立体异构体，尚不清楚该抑制剂如何结合转运蛋白。在这里，我们报告了与人FABP5和FABP7分别以2.2和1.9Å分辨率复合的SBFI-26的共晶体结构。我们发现只有（S）-SBFI-26存在于晶体结构中。该抑制剂在很大程度上模拟了脂肪酸的结合模式，但它也具有一些独特的相互作用。值得注意的是，FABP7复合物证实了先前通过虚拟筛选预测的规范位点上的配体结合姿势的关键方面。在FABP5中，出人意料地发现SBFI-26除了在规范配体结合口袋处结合外，还在底物进入入口区域结合。我们的结构能和结合能分析表明，R和S形式似乎均能很好地结合转运蛋白。我们建议在晶体结构中观察到的S对映异构体可能是结晶过程选择性地掺入（S）-SBFI-26-FABP络合到正在生长的晶格中，或者S对映异构体与门户部位的结合比与经典部位的结合更快，从而导致S对映异构体与经典部位的结合的局部浓度增加。我们的工作揭示了SBFI-26在其目标转运蛋白中的两种结合姿势。这些知识将指导基于SBFI-26支架的更有效的FABP抑制剂的开发。

"点击查看英文标题和摘要"

The Antinociceptive Agent SBFI-26 Binds to Anandamide Transporters FABP5 and FABP7 at Two Different Sites

Human FABP5 and FABP7 are intracellular endocannabinoid transporters. SBFI-26 is an α-truxillic acid 1-naphthyl monoester that competitively inhibits the activities of FABP5 and FABP7 and produces antinociceptive and anti-inflammatory effects in mice. The synthesis of SBFI-26 yields several stereoisomers, and it is not known how the inhibitor binds the transporters. Here we report co-crystal structures of SBFI-26 in complex with human FABP5 and FABP7 at 2.2 and 1.9 Å resolution, respectively. We found that only (S)-SBFI-26 was present in the crystal structures. The inhibitor largely mimics the fatty acid binding pattern, but it also has several unique interactions. Notably, the FABP7 complex corroborates key aspects of the ligand binding pose at the canonical site previously predicted by virtual screening. In FABP5, SBFI-26 was unexpectedly found to bind at the substrate entry portal region in addition to binding at the canonical ligand-binding pocket. Our structural and binding energy analyses indicate that both R and S forms appear to bind the transporter equally well. We suggest that the S enantiomer observed in the crystal structures may be a result of the crystallization process selectively incorporating the (S)-SBFI-26–FABP complexes into the growing lattice, or that the S enantiomer may bind to the portal site more rapidly than to the canonical site, leading to an increased local concentration of the S enantiomer for binding to the canonical site. Our work reveals two binding poses of SBFI-26 in its target transporters. This knowledge will guide the development of more potent FABP inhibitors based upon the SBFI-26 scaffold.

更新日期：2017-06-29

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