与磷酰胺脒或硫磷酰胺素复合的可溶性兔肾肽酶的结构。
Structures of soluble rabbit neprilysin complexed with phosphoramidon or thiorphan.
作者信息
Labiuk Shaunivan L, Sygusch Jurgen, Grochulski Pawel
机构信息
Canadian Light Source, 44 Innovation Boulevard, Saskatoon, SK S7N 2V3, Canada.
Biochimie et Médecine Moléculaire, Université de Montréal, CP 6128, Station Centre-Ville, Montréal, QC H3C 3J7, Canada.
出版信息
Acta Crystallogr F Struct Biol Commun. 2019 Jun 1;75(Pt 6):405-411. doi: 10.1107/S2053230X19006046. Epub 2019 May 10.
Abstract
Neutral endopeptidase (neprilysin; NEP) is a proteinase that cleaves a wide variety of peptides and has been implicated in Alzheimer's disease, cardiovascular conditions, arthritis and other inflammatory diseases. The structure of the soluble extracellular domain (residues 55-750) of rabbit neprilysin was solved both in its native form at 2.1 Å resolution, and bound to the inhibitors phosphoramidon and thiorphan at 2.8 and 3.0 Å resolution, respectively. Consistent with the extracellular domain of human neprilysin, the structure reveals a large central cavity which contains the active site and the location for inhibitor binding.
摘要
中性内肽酶（脑啡肽酶；NEP）是一种能切割多种肽类的蛋白酶，与阿尔茨海默病、心血管疾病、关节炎及其他炎症性疾病有关。兔脑啡肽酶可溶性细胞外结构域（第55 - 750位氨基酸残基）的结构已被解析，其天然形式的分辨率为2.1 Å，与抑制剂膦甲脒和硫氧苯丙氨酸结合时的分辨率分别为2.8 Å和3.0 Å。与人类脑啡肽酶的细胞外结构域一致，该结构显示出一个大的中央腔，其中包含活性位点和抑制剂结合位点。
相似文献
1
Structures of soluble rabbit neprilysin complexed with phosphoramidon or thiorphan.与磷酰胺脒或硫磷酰胺素复合的可溶性兔肾肽酶的结构。
Acta Crystallogr F Struct Biol Commun. 2019 Jun 1;75(Pt 6):405-411. doi: 10.1107/S2053230X19006046. Epub 2019 May 10.
2
Structure of human neutral endopeptidase (Neprilysin) complexed with phosphoramidon.与磷酰胺素复合的人中性内肽酶（肾素-血管紧张素系统肽酶）的结构。
J Mol Biol. 2000 Feb 18;296(2):341-9. doi: 10.1006/jmbi.1999.3492.
3
Mutagenesis of Glu403 to Cys in rabbit neutral endopeptidase-24.11 (neprilysin) creates a disulphide-linked homodimer: analogy with endothelin-converting enzyme.将兔中性内肽酶-24.11（肾素-血管紧张素系统的肽酶）中的谷氨酸403突变为半胱氨酸会产生二硫键连接的同型二聚体：与内皮素转化酶的类比。
Biochem J. 1997 Nov 1;327 ( Pt 3)(Pt 3):925-9. doi: 10.1042/bj3270925.
4
Neprilysin degrades both amyloid beta peptides 1-40 and 1-42 most rapidly and efficiently among thiorphan- and phosphoramidon-sensitive endopeptidases.在硫代磷酰胆碱和磷酰胺脒敏感的内肽酶中，中性内肽酶能最快速且高效地降解淀粉样β肽1-40和1-42。
J Biol Chem. 2001 Jun 15;276(24):21895-901. doi: 10.1074/jbc.M008511200. Epub 2001 Mar 6.
5
Evidence that Asn542 of neprilysin (EC 3.4.24.11) is involved in binding of the P2' residue of substrates and inhibitors.有证据表明，中性内肽酶（EC 3.4.24.11）的天冬酰胺542参与底物和抑制剂P2'残基的结合。
Biochem J. 1995 Oct 15;311 ( Pt 2)(Pt 2):623-7. doi: 10.1042/bj3110623.
6
Evidence by site-directed mutagenesis that arginine 203 of thermolysin and arginine 717 of neprilysin (neutral endopeptidase) play equivalent critical roles in substrate hydrolysis and inhibitor binding.定点诱变证据表明，嗜热菌蛋白酶的精氨酸203和中性内肽酶（肾肽酶）的精氨酸717在底物水解和抑制剂结合中起同等关键作用。
Biochemistry. 1997 Nov 11;36(45):13938-45. doi: 10.1021/bi9712495.
7
pH- and time-dependent inhibition of rat kidney neutral endoprotease 24.11 by thiorphan and phosphoramidon.硫磷酰胺和磷酰胺对大鼠肾脏中性内肽酶24.11的pH值和时间依赖性抑制作用。
Life Sci. 1989;45(22):2109-14. doi: 10.1016/0024-3205(89)90076-3.
8
A three-dimensional model of endothelin-converting enzyme (ECE) based on the X-ray structure of neutral endopeptidase 24.11 (NEP).基于中性内肽酶24.11（NEP）的X射线结构构建的内皮素转化酶（ECE）三维模型。
Protein Eng. 2001 May;14(5):337-41. doi: 10.1093/protein/14.5.337.
9
Soluble recombinant neprilysin induces aggrecanase-mediated cleavage of aggrecan in cartilage explant cultures.可溶性重组中性内肽酶在软骨外植体培养物中诱导聚糖酶介导的蛋白聚糖裂解。
Arch Biochem Biophys. 2001 Dec 15;396(2):178-86. doi: 10.1006/abbi.2001.2608.
10
Characterization of the enzyme involved in the processing of big endothelin-1 in human lung epithelial cells.人肺上皮细胞中参与大内皮素-1加工的酶的特性研究。
Pulm Pharmacol Ther. 1998 Apr-Jun;11(2-3):209-13. doi: 10.1006/pupt.1998.0140.
引用本文的文献
1
Design of Novel Mercapto-3-phenylpropanoyl Dipeptides as Dual Angiotensin-Converting Enzyme C-Domain-Selective/Neprilysin Inhibitors.新型巯基-3-苯基丙酰二肽作为双重血管紧张素转换酶C结构域选择性/中性肽链内切酶抑制剂的设计
J Med Chem. 2025 Apr 10;68(7):7720-7736. doi: 10.1021/acs.jmedchem.5c00329. Epub 2025 Apr 1.
2
Comprehensive review on neprilysin (NEP) inhibitors: design, structure-activity relationships, and clinical applications.中性内肽酶（NEP）抑制剂综述：设计、构效关系及临床应用
Front Pharmacol. 2024 Dec 23;15:1501407. doi: 10.3389/fphar.2024.1501407. eCollection 2024.
3
Structural analysis of Mycobacterium tuberculosis M13 metalloprotease Zmp1 open states.结核分枝杆菌 M13 金属蛋白酶 Zmp1 开放态的结构分析。
Structure. 2021 Jul 1;29(7):709-720.e3. doi: 10.1016/j.str.2020.12.002. Epub 2020 Dec 29.
4
Molecular Basis for Omapatrilat and Sampatrilat Binding to Neprilysin-Implications for Dual Inhibitor Design with Angiotensin-Converting Enzyme.奥美沙坦酯和桑普沙坦与 Neprilysin 结合的分子基础-对血管紧张素转换酶双重抑制剂设计的启示。
J Med Chem. 2020 May 28;63(10):5488-5500. doi: 10.1021/acs.jmedchem.0c00441. Epub 2020 May 8.
本文引用的文献
1
High resolution crystal structure of substrate-free human neprilysin.人组织型纤溶酶原激活物抑制剂无底物复合物的高分辨率晶体结构
J Struct Biol. 2018 Oct;204(1):19-25. doi: 10.1016/j.jsb.2018.06.004. Epub 2018 Jun 12.
2
Mycobacterium tuberculosis Molecular Determinants of Infection, Survival Strategies, and Vulnerable Targets.结核分枝杆菌 感染的分子决定因素、生存策略及易损靶点
Pathogens. 2018 Feb 1;7(1):17. doi: 10.3390/pathogens7010017.
3
Combined Inhibition of the Renin-Angiotensin System and Neprilysin Positively Influences Complex Mitochondrial Adaptations in Progressive Experimental Heart Failure.肾素-血管紧张素系统与中性肽链内切酶的联合抑制对进行性实验性心力衰竭中复杂的线粒体适应性产生积极影响。
PLoS One. 2017 Jan 11;12(1):e0169743. doi: 10.1371/journal.pone.0169743. eCollection 2017.
4
Development of immune-biomarkers of pulmonary tuberculosis in a rabbit model.兔模型中肺结核免疫生物标志物的开发
Tuberculosis (Edinb). 2016 Dec;101:1-7. doi: 10.1016/j.tube.2016.07.008. Epub 2016 Jul 26.
5
Processing of X-ray diffraction data collected in oscillation mode.振荡模式下收集的X射线衍射数据的处理。
Methods Enzymol. 1997;276:307-26. doi: 10.1016/S0076-6879(97)76066-X.
6
Structure of neprilysin in complex with the active metabolite of sacubitril.利那普利酶与沙库巴曲缬沙坦活性代谢物复合物的结构。
Sci Rep. 2016 Jun 15;6:27909. doi: 10.1038/srep27909.
7
Amyloid-clearing proteins and their epigenetic regulation as a therapeutic target in Alzheimer's disease.淀粉样蛋白清除蛋白及其在阿尔茨海默病中的表观遗传调控作为治疗靶点。
Front Aging Neurosci. 2014 Sep 17;6:235. doi: 10.3389/fnagi.2014.00235. eCollection 2014.
8
Engineering neprilysin activity and specificity to create a novel therapeutic for Alzheimer's disease.设计中性内肽酶的活性和特异性以开发一种治疗阿尔茨海默病的新型疗法。
PLoS One. 2014 Aug 4;9(8):e104001. doi: 10.1371/journal.pone.0104001. eCollection 2014.
9
Endothelial permeability in vitro and in vivo: protective actions of ANP and omapatrilat in experimental atherosclerosis.血管内皮通透性的体外和体内研究：心钠肽和奥马曲拉在实验性动脉粥样硬化中的保护作用。
Peptides. 2013 Oct;48:21-6. doi: 10.1016/j.peptides.2013.07.020. Epub 2013 Aug 6.
10
Antihypertrophic effects of combined inhibition of the renin-angiotensin system (RAS) and neutral endopeptidase (NEP) in progressive, tachycardia-induced experimental heart failure.联合抑制肾素-血管紧张素系统（RAS）和中性内肽酶（NEP）对进行性、心动过速诱导的实验性心力衰竭的抗肥厚作用。
Naunyn Schmiedebergs Arch Pharmacol. 2012 Nov;385(11):1117-25. doi: 10.1007/s00210-012-0791-6. Epub 2012 Aug 16.
Zotero 插件