阿司匹林及其衍生物与脂肪酸结合蛋白4复合物的晶体学研究

黄佩; 李敏军; 左刚; 郭豪杰; 周欢; 谢牧云; 郁峰; 徐春艳; 何建华

doi:10.11889/j.0253-3219.2016.hjs.39.080101

您当前的位置：

首页 >

文章列表页 >

阿司匹林及其衍生物与脂肪酸结合蛋白4复合物的晶体学研究

同步辐射技术及应用 | 更新时间：2021-05-24

- 阿司匹林及其衍生物与脂肪酸结合蛋白4复合物的晶体学研究
  封面论文
- Crystallography study of the complexes of human fatty acid binding protein 4 with aspirin and its derivative
- 核技术 2016年39卷第8期文章编号：080101
- 作者机构：
  
  1.中国科学院上海应用物理研究所张江园区上海 201204
  2.中国科学院大学北京 100049
- 作者简介：
  
  [ "黄佩, 女, 1990年出生, 2013年毕业于西北大学, 现为硕士研究生, 研究方向为生物大分子晶体学", "HUANG Pei, female, born in 1990, graduated from Northwestern University in 2013, master student, focusing on macromolecular crystallography" ]
  李敏军, E-mail:liminjun@sinap.ac.cn LI Minjun, E-mail: liminjun@sinap.ac.cn
  何建华, E-mail:hejh@sinap.ac.cn HE Jianhua, E-mail: hejh@sinap.ac.cn
- 基金信息：
  
  国家自然科学基金(No.31100528);国家自然科学基金(No.31371260)
- DOI：10.11889/j.0253-3219.2016.hjs.39.080101
  中图分类号： TL99
- 收稿日期：2016-04-18，
  
  修回日期：2016-04-28，
  
  纸质出版日期：2016-08
- 稿件说明：
移动端阅览
黄佩, 李敏军, 左刚, 等. 阿司匹林及其衍生物与脂肪酸结合蛋白4复合物的晶体学研究[J]. 核技术, 2016,39(8):080101

Pei HUANG, Minjun LI, Gang ZUO, et al. Crystallography study of the complexes of human fatty acid binding protein 4 with aspirin and its derivative[J]. Nuclear techniques, 2016, 39(8): 080101
黄佩, 李敏军, 左刚, 等. 阿司匹林及其衍生物与脂肪酸结合蛋白4复合物的晶体学研究[J]. 核技术, 2016,39(8):080101 DOI： 10.11889/j.0253-3219.2016.hjs.39.080101.

Pei HUANG, Minjun LI, Gang ZUO, et al. Crystallography study of the complexes of human fatty acid binding protein 4 with aspirin and its derivative[J]. Nuclear techniques, 2016, 39(8): 080101 DOI： 10.11889/j.0253-3219.2016.hjs.39.080101.

摘要

脂肪酸结合蛋白4（Fatty Acid Binding Protein 4

FABP4）作为脂肪酸伴侣，参与调节脂肪酸代谢、运输、脂介导的信号转导以及巨噬细胞的炎症反应。该蛋白的抑制经常作为治疗脂肪代谢疾病的有效方案。本文报道了经典非甾体抗炎药阿司匹林及其水解物水杨酸与FABP4蛋白复合物的晶体结构，从而推测阿司匹林可能通过FABP4蛋白途径抑制动脉粥样硬化的分子机制。结构分析进一步阐明了FABP4蛋白疏水残基Phe16苯环侧链与水杨酸之间的C-H-π相互作用比亲水位点静电相互作用提供更稳定的结合。该发现为设计更高选择性FABP4抑制剂提供了新的途径。

Abstract

Background:

Fatty acid binding protein 4 (FABP4)

as fatty acid chaperone

plays center roles in lipid transport

lipolysis and liposynthesis

and it has been proved to be involved in the lipid signaling and inflammatory responses. Inhibitors of FABP4 are promising treatments for the diabetes and atherosclerosis.

Purpose:

The aim is to reveal the structural conformation of aspirin and salicylic acid binding to the FABP4

and to explore the novel structural features for the design of high-selective FABP4 inhibitors.

Methods:

Single crystal X-ray diffraction is applied to solve the structure of the ligand-protein complexes.

Results:

We have determined the crystal structures of FABP4 in complex with aspirin and its derivative

and from which a special C-H-πinteraction between the residues Phe16

Arg126 and the benzyl ring of aspirin has been defined.

Conclusion:

The complex structures of FABP4 bound with aspirin and its derivative show that the edge-to-face C-H-πinteraction between the residues Phe16

Arg126 and the benzyl ring of aspirin is a critical intermolecular force between the ligand-FABP4 interactions

which enables us to consciously apply these interactions in hit and lead optimization in rational structure based drug design.

关键词

Keywords

references

M Furuhashi , G S Hotamisligil . Fatty acid-binding proteins:role in metabolic diseases and potential as drug targets . Nature Review Drug Discovery , 2008 . 7 ( 6 ): 489 - 503 . DOI: 10.1038/nrd2589 http://doi.org/10.1038/nrd2589 .

A W Zimmerman , H J Veerkamp . New insights into the structure and function of fatty acid-binding proteins . Cellular and Molecular Life Sciences , 2002 . 59 1096 - 1116 . DOI: 10.1007/s00018-002-8490-y http://doi.org/10.1007/s00018-002-8490-y .

R L Smathers , D R Petersen . The human fatty acid-binding protein family:evolutionary divergences and functions . Human Genomics , 2010 . 5 ( 3 ): 170 - 191 . http://cn.bing.com/academic/profile?id=1972168184&encoded=0&v=paper_preview&mkt=zh-cn .

M Furuhashi , S Saitoh , K Shimamoto , . Fatty Acid-Binding Protein 4(FABP4):pathophysiological insights and potent clinical biomarker of metabolic and cardiovascular diseases . Clinical Medicine Insights:Cardiology , 2015 . 8 ( S3 ): 23 - 33 . DOI: 10.4137/cmc.s1067 http://doi.org/10.4137/cmc.s1067 .

L Makowski , J B Boord , K Maeda , . Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis . Nature Medicine , 2001 . 7 ( 6 ): 699 - 705 . DOI: 10.1038/nm89076 http://doi.org/10.1038/nm89076 .

S D Ayers , K L Nedrow , R E Gillilan , . Continuous nucleocytoplasmic shuttling underlies transcriptional activation of PPARγby FABP4 . Biochemistry , 2007 . 46 ( 23 ): 6744 - 6752 . DOI: 10.1021/bi700047a http://doi.org/10.1021/bi700047a .

L Gan , Z Liu , W Cao , . FABP4 reversed the regulation of leptin on mitochondrial fatty acid oxidation in mice adipocytes . Scientific Reports , 2015 . 5 13588 DOI: 10.1038/srep13588 http://doi.org/10.1038/srep13588 .

M Furuhashi , G Tuncman , C Z Gorgun , . Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2 . Nature , 2007 . 447 ( 7147 ): 959 - 965 . DOI: 10.1038/nature05844 http://doi.org/10.1038/nature05844 .

F Lehmann , S Haile , E Axen , . Discovery of inhibitors of human adipocyte fatty acid-binding protein, a potential type 2 diabetes target . Bioorganic & Medicinal Chemistry Letters , 2004 . 14 ( 17 ): 4445 - 4448 . DOI: 10.1016/j.bmcl.2004.06.057 http://doi.org/10.1016/j.bmcl.2004.06.057 .

E Marr , M Tardie , M Carty , . Expression, purification, crystallization and structure of human adipocyte lipid-binding protein (aP2) . Acta Crystallographica Section F , 2006 . 62 ( 11 ): 1058 - 1060 . DOI: 10.1107/S1744309106038656 http://doi.org/10.1107/S1744309106038656 .

H Cai , Q Liu , D Gao , . Novel fatty acid binding protein 4(FABP4) inhibitors:virtual screening, synthesis and crystal structure determination . European Journal of Medicinal Chemistry , 2015 . 90 241 - 250 . DOI: 10.1016/j.ejmech.2014.11.020 http://doi.org/10.1016/j.ejmech.2014.11.020 .

J M Gonzalez , S Z Fisher . Structural analysis of ibuprofen binding to human adipocyte fatty-acid binding protein (FABP4) . Acta Crystallographica Section F , 2015 . 71 ( 2 ): 163 - 170 . DOI: 10.1107/S2053230X14027897 http://doi.org/10.1107/S2053230X14027897 .

杨钰 , 于晓玲 . 阿司匹林与动脉粥样硬化 . 医学综述 , 2006 . 12 ( 19 ): 1194 - 1196 . http://www.cqvip.com/qk/98202x/200619/23022912.html .

Yu YANG , Xiaoling YU . Aspirin and atherosclerosis . Medical Recapitulate , 2006 . 12 ( 19 ): 1194 - 1196 . http://www.cqvip.com/qk/98202x/200619/23022912.html .

E Marr , M Tardie , M Carty , . Expression, purification, crystallization and structure of human adipocyte lipid-binding protein (aP2) . Acta Crystallographica Section F , 2006 . 62 ( Pt11 ): 1058 - 1060 . DOI: 10.1107/S1744309106038656 http://doi.org/10.1107/S1744309106038656 .

Q S Wang , F Yu , S Huang , . The macromolecular crystallography beamline of SSRF . Nuclear Science and Techniques , 2015 . 26 ( 1 ): 010102 DOI: 10.13538/j.1001-8042/nst.26.010102 http://doi.org/10.13538/j.1001-8042/nst.26.010102 .

Z Otwinowski , W Minor . Processing of X-ray diffraction data collected in oscillation mode . Macromolecular Crystallography , 1997 . 276 307 - 326 . DOI: 10.1016/S0076-6879(97)76066-X http://doi.org/10.1016/S0076-6879(97)76066-X .

W Kabsch . Integration, scaling, space-group assignment and post-refinement . Acta Crystallographica Section D , 2010 . 66 ( Pt2 ): 133 - 144 . DOI: 10.1107/S0907444909047374 http://doi.org/10.1107/S0907444909047374 .

Computational Project N Collaborative . The CCP4 suite:programs for protein crystallography . Acta Crystallographica Section D , 1994 . 50 ( 5 ): 760 - 763 . DOI: 10.1107/S0907444994003112 http://doi.org/10.1107/S0907444994003112 .

P D Adams , P V Afonine , G Bunkóczi , . PHENIX:a comprehensive Python-based system for macromolecular structure solution . Acta Crystallographica Section D , 2010 . 66 ( 2 ): 213 - 221 . DOI: 10.1107/S0907444909052925 http://doi.org/10.1107/S0907444909052925 .

P Emsley , K Cowtan . Coot:model-building tools for molecular graphics . Acta Crystallographica Section D , 2004 . 60 ( 12-1 ): 2126 - 2132 . DOI: 10.1107/S0907444904019158 http://doi.org/10.1107/S0907444904019158 .

Delano W L. The PyMOL molecular graphic system[C]. Palo Alto, CA:Delano Scientific, 2002

W B Jennings , N O'Connell , J F Malone , . An evaluation of substituent effects on aromatic edge-to-face interactions and CF-[small pi] versus CH-[small pi] interactions using an imino torsion balance model . Organic & Biomolecular Chemistry , 2013 . 11 ( 32 ): 5278 - 5291 . DOI: 10.1039/C3OB40535D http://doi.org/10.1039/C3OB40535D .

M Brandl , M S Weiss , A Jabs , . C-h…π-interactions in proteins . Journal of Molecular Biology , 2001 . 307 ( 1 ): 357 - 377 . DOI: 10.1006/jmbi.2000.4473 http://doi.org/10.1006/jmbi.2000.4473 .

浏览量

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

暂无数据