• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

人类免疫缺陷病毒1型合成蛋白酶与基于底物的羟乙胺抑制剂复合物的X射线晶体学结构

X-ray crystallographic structure of a complex between a synthetic protease of human immunodeficiency virus 1 and a substrate-based hydroxyethylamine inhibitor.

作者信息

Swain A L, Miller M M, Green J, Rich D H, Schneider J, Kent S B, Wlodawer A

机构信息

Crystallography Laboratory, National Cancer Institute-Frederick Cancer Research and Development Center, MD 21702.

出版信息

Proc Natl Acad Sci U S A. 1990 Nov;87(22):8805-9. doi: 10.1073/pnas.87.22.8805.

DOI:10.1073/pnas.87.22.8805
PMID:2247451
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC55048/
Abstract

The structure of a crystal complex of the chemically synthesized protease of human immunodeficiency virus 1 with a heptapeptide-derived inhibitor bound in the active site has been determined. The sequence of the inhibitor JG-365 is Ac-Ser-Leu-Asn-Phe-psi[CH(OH)CH2N]-Pro-Ile-Val-OMe; the Ki is 0.24 nM. The hydroxyethylamine moiety, in place of the normal scissile bond of the substrate, is believed to mimic a tetrahedral reaction intermediate. The structure of the complex has been refined to an R factor of 0.146 at 2.4-A resolution by using restrained least squares with rms deviations in bond lengths of 0.02 A and bond angles of 4. The bound inhibitor diastereomer has the S configuration at the hydroxyethylamine chiral carbon, and the hydroxyl group is positioned between the active site aspartate carboxyl groups within hydrogen bonding distance. Comparison of this structure with a reduced peptide bond inhibitor-protease complex indicates that these contacts confer the exceptional binding strength of JG-365.

摘要

已确定化学合成的人类免疫缺陷病毒1蛋白酶与结合在活性位点的七肽衍生抑制剂形成的晶体复合物的结构。抑制剂JG-365的序列为Ac-Ser-Leu-Asn-Phe-psi[CH(OH)CH2N]-Pro-Ile-Val-OMe；其抑制常数Ki为0.24 nM。羟乙胺部分取代了底物的正常可裂解键，被认为模拟了四面体反应中间体。通过使用约束最小二乘法，在2.4埃分辨率下将复合物的结构精修至R因子为0.146，键长的均方根偏差为0.02埃，键角为4°。结合的抑制剂非对映异构体在羟乙胺手性碳上具有S构型，并且羟基位于活性位点天冬氨酸羧基之间的氢键距离内。将该结构与还原肽键抑制剂-蛋白酶复合物进行比较表明，这些相互作用赋予了JG-365非凡的结合强度。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59fe/55048/a9ae89aff7e3/pnas01047-0129-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59fe/55048/a9ae89aff7e3/pnas01047-0129-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59fe/55048/a9ae89aff7e3/pnas01047-0129-a.jpg

相似文献

1
X-ray crystallographic structure of a complex between a synthetic protease of human immunodeficiency virus 1 and a substrate-based hydroxyethylamine inhibitor.人类免疫缺陷病毒1型合成蛋白酶与基于底物的羟乙胺抑制剂复合物的X射线晶体学结构
Proc Natl Acad Sci U S A. 1990 Nov;87(22):8805-9. doi: 10.1073/pnas.87.22.8805.
2
Structure at 2.5-A resolution of chemically synthesized human immunodeficiency virus type 1 protease complexed with a hydroxyethylene-based inhibitor.与基于羟乙烯的抑制剂复合的化学合成人免疫缺陷病毒1型蛋白酶的2.5埃分辨率结构。
Biochemistry. 1991 Feb 12;30(6):1600-9. doi: 10.1021/bi00220a023.
3
Crystal structure of a complex of HIV-1 protease with a dihydroxyethylene-containing inhibitor: comparisons with molecular modeling.HIV-1蛋白酶与含二羟基乙烯抑制剂复合物的晶体结构：与分子模拟的比较
Protein Sci. 1992 Aug;1(8):1061-72. doi: 10.1002/pro.5560010811.
4
Role of hydroxyl group and R/S configuration of isostere in binding properties of HIV-1 protease inhibitors.羟基和等排体的R/S构型在HIV-1蛋白酶抑制剂结合特性中的作用。
Eur J Biochem. 2004 Nov;271(22):4451-61. doi: 10.1111/j.1432-1033.2004.04384.x.
5
Hydroxyethylene isostere inhibitors of human immunodeficiency virus-1 protease: structure-activity analysis using enzyme kinetics, X-ray crystallography, and infected T-cell assays.人免疫缺陷病毒-1蛋白酶的羟乙烯电子等排体抑制剂：利用酶动力学、X射线晶体学和感染T细胞试验进行的构效关系分析
Biochemistry. 1992 Jul 28;31(29):6646-59. doi: 10.1021/bi00144a004.
6
Crystal structure of human immunodeficiency virus (HIV) type 2 protease in complex with a reduced amide inhibitor and comparison with HIV-1 protease structures.与还原型酰胺抑制剂复合的2型人类免疫缺陷病毒（HIV）蛋白酶的晶体结构及与HIV-1蛋白酶结构的比较。
Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8387-91. doi: 10.1073/pnas.90.18.8387.
7
Insights from atomic-resolution X-ray structures of chemically synthesized HIV-1 protease in complex with inhibitors.化学合成的HIV-1蛋白酶与抑制剂复合物的原子分辨率X射线结构的见解。
J Mol Biol. 2007 Oct 26;373(3):573-86. doi: 10.1016/j.jmb.2007.07.054. Epub 2007 Aug 2.
8
The crystallographic structure of the protease from human immunodeficiency virus type 2 with two synthetic peptidic transition state analog inhibitors.来自2型人类免疫缺陷病毒的蛋白酶与两种合成肽类过渡态类似物抑制剂的晶体结构
J Biol Chem. 1993 Jun 25;268(18):13103-9.
9
X-ray analyses of aspartic proteinases. III Three-dimensional structure of endothiapepsin complexed with a transition-state isostere inhibitor of renin at 1.6 A resolution.天冬氨酸蛋白酶的X射线分析。III. 以1.6埃分辨率解析的与肾素过渡态类似物抑制剂复合的内硫醇蛋白酶的三维结构。
J Mol Biol. 1990 Dec 20;216(4):1017-29. doi: 10.1016/S0022-2836(99)80017-5.
10
On the role of the R configuration of the reaction-intermediate isostere in HIV-1 protease-inhibitor binding: X-ray structure at 2.0 A resolution.反应中间体电子等排体的R构型在HIV-1蛋白酶抑制剂结合中的作用：2.0埃分辨率的X射线结构
Acta Crystallogr D Biol Crystallogr. 2006 May;62(Pt 5):489-97. doi: 10.1107/S0907444906006718. Epub 2006 Apr 19.

引用本文的文献

1
Prediction and molecular field view of drug resistance in HIV-1 protease mutants.HIV-1 蛋白酶突变体耐药性的预测和分子场分析。
Sci Rep. 2022 Feb 21;12(1):2913. doi: 10.1038/s41598-022-07012-x.
2
Structural Insights to Human Immunodeficiency Virus (HIV-1) Targets and Their Inhibition.结构洞察人类免疫缺陷病毒 (HIV-1) 靶点及其抑制。
Adv Exp Med Biol. 2021;1322:63-95. doi: 10.1007/978-981-16-0267-2_3.
3
Dimer Interface Organization is a Main Determinant of Intermonomeric Interactions and Correlates with Evolutionary Relationships of Retroviral and Retroviral-Like Ddi1 and Ddi2 Proteases.

本文引用的文献

1
Potent new inhibitors of human renin.新型强效人肾素抑制剂
Nature. 1982 Oct 7;299(5883):555-7. doi: 10.1038/299555a0.
2
Stereochemically restrained refinement of macromolecular structures.大分子结构的立体化学受限精修
Methods Enzymol. 1985;115:252-70. doi: 10.1016/0076-6879(85)15021-4.
3
Human renin: a new class of inhibitors.人肾素：一类新型抑制剂。
二聚体界面组织是决定单体间相互作用的主要因素，与逆转录病毒和类逆转录病毒 Ddi1 和 Ddi2 蛋白酶的进化关系相关。
Int J Mol Sci. 2020 Feb 17;21(4):1352. doi: 10.3390/ijms21041352.
4
Stapled Peptides Inhibitors: A New Window for Target Drug Discovery.钉肽抑制剂：靶向药物发现的新窗口。
Comput Struct Biotechnol J. 2019 Feb 19;17:263-281. doi: 10.1016/j.csbj.2019.01.012. eCollection 2019.
5
Structural studies of the yeast DNA damage-inducible protein Ddi1 reveal domain architecture of this eukaryotic protein family.酵母 DNA 损伤诱导蛋白 Ddi1 的结构研究揭示了该蛋白家族的结构域架构。
Sci Rep. 2016 Sep 20;6:33671. doi: 10.1038/srep33671.
6
Discovery of MK-8718, an HIV Protease Inhibitor Containing a Novel Morpholine Aspartate Binding Group.MK-8718的发现，一种含有新型吗啉天冬氨酸结合基团的HIV蛋白酶抑制剂。
ACS Med Chem Lett. 2016 May 9;7(7):702-7. doi: 10.1021/acsmedchemlett.6b00135. eCollection 2016 Jul 14.
7
Integrated analysis of residue coevolution and protein structures capture key protein sectors in HIV-1 proteins.残基协同进化与蛋白质结构的综合分析揭示了HIV-1蛋白中的关键蛋白质区域。
PLoS One. 2015 Feb 11;10(2):e0117506. doi: 10.1371/journal.pone.0117506. eCollection 2015.
8
Current perspectives on HIV-1 antiretroviral drug resistance.关于HIV-1抗逆转录病毒药物耐药性的当前观点。
Viruses. 2014 Oct 24;6(10):4095-139. doi: 10.3390/v6104095.
9
Investigation on the mechanism for the binding and drug resistance of wild type and mutations of G86 residue in HIV-1 protease complexed with Darunavir by molecular dynamic simulation and free energy calculation.基于分子动力学模拟和自由能计算研究野生型和 HIV-1 蛋白酶 G86 残基突变体与达芦那韦复合物的结合和耐药机制。
J Mol Model. 2014 Feb;20(2):2122. doi: 10.1007/s00894-014-2122-y. Epub 2014 Feb 14.
10
Identification of HIV inhibitors guided by free energy perturbation calculations.基于自由能微扰计算的 HIV 抑制剂鉴定。
Curr Pharm Des. 2012;18(9):1199-216. doi: 10.2174/138161212799436421.
Biochem Biophys Res Commun. 1986 Jan 14;134(1):71-7. doi: 10.1016/0006-291x(86)90528-0.
4
Renin inhibitors.肾素抑制剂
Pharm Res. 1987 Oct;4(5):364-74. doi: 10.1023/a:1016422009662.
5
On the rational design of renin inhibitors: X-ray studies of aspartic proteinases complexed with transition-state analogues.关于肾素抑制剂的合理设计：与过渡态类似物复合的天冬氨酸蛋白酶的X射线研究。
Biochemistry. 1987 Sep 8;26(18):5585-90. doi: 10.1021/bi00392a001.
6
Binding of a reduced peptide inhibitor to the aspartic proteinase from Rhizopus chinensis: implications for a mechanism of action.还原型肽抑制剂与华根霉天冬氨酸蛋白酶的结合：对作用机制的启示
Proc Natl Acad Sci U S A. 1987 Oct;84(20):7009-13. doi: 10.1073/pnas.84.20.7009.
7
A structural model for the retroviral proteases.逆转录病毒蛋白酶的结构模型。
Nature. 1987;329(6137):351-4. doi: 10.1038/329351a0.
8
Enzymatic activity of a synthetic 99 residue protein corresponding to the putative HIV-1 protease.一种与假定的HIV-1蛋白酶相对应的99个残基合成蛋白的酶活性。
Cell. 1988 Jul 29;54(3):363-8. doi: 10.1016/0092-8674(88)90199-7.
9
Synthetic peptides as substrates and inhibitors of human immune deficiency virus-1 protease.合成肽作为人类免疫缺陷病毒-1蛋白酶的底物和抑制剂。
J Biol Chem. 1988 Dec 5;263(34):17905-8.
10
Chemical synthesis of peptides and proteins.肽和蛋白质的化学合成
Annu Rev Biochem. 1988;57:957-89. doi: 10.1146/annurev.bi.57.070188.004521.