典型文献
Distal mutation V486M disrupts the catalytic activity of DPP4 by affecting the flap of the propeller domain
文献摘要：
Dipeptidyl peptidase-4(DPP4)plays a crucial role in regulating the bioactivity of glucagon-like peptide-1(GLP-1)that enhances insulin secretion and pancreatic β-cell proliferation,making it a therapeutic target for type 2 diabetes.Although the crystal structure of DPP4 has been determined,its structure-function mechanism is largely unknown.Here,we examined the biochemical properties of sporadic human DPP4 mutations distal from its catalytic site,among which V486M ablates DPP4 dimerization and causes loss of enzymatic activity.Unbiased molecular dynamics simulations revealed that the distal V486M mutation induces a local conformational collapse in a β-propeller loop(residues 234-260,defined as the flap)and disrupts the dimerization of DPP4.The"open/closed"conformational transitions of the flap whereby capping the active site,are involved in the enzymatic activity of DPP4.Further site-directed mutagenesis guided by theoretical predictions verified the importance of the conformational dynamics of the flap for the enzymatic activity of DPP4.Therefore,the current studies that combined theoretical modeling and experimental identification,provide important insights into the biological function of DPP4 and allow for the evaluation of directed DPP4 genetic mutations before initiating clinical applications and drug development.
文献关键词：
中图分类号：
作者姓名：
Teng-teng Li;Cheng Peng;Ji-qiu Wang;Zhi-jian Xu;Ming-bo Su;Jia Li;Wei-liang Zhu;Jing-ya Li
作者机构：
State Key Laboratory of Drug Research,the National Drug Screening Center,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;School of Life Science and Technology,ShanghaiTech University,Shanghai 201210,China;CAS Key Laboratory of Receptor Research;Drug Discovery and Design Center,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;Schoolof Pharmacy,University of Chinese Academy of Sciences,Beijing 100049,China
文献出处：
引用格式：
[1]Teng-teng Li;Cheng Peng;Ji-qiu Wang;Zhi-jian Xu;Ming-bo Su;Jia Li;Wei-liang Zhu;Jing-ya Li-.Distal mutation V486M disrupts the catalytic activity of DPP4 by affecting the flap of the propeller domain)[J].中国药理学报（英文版）,2022(08):2147-2155
A类：
V486M,ablates,Unbiased
B类：
Distal,disrupts,catalytic,DPP4,affecting,flap,propeller,domain,Dipeptidyl,peptidase,plays,crucial,role,regulating,bioactivity,glucagon,like,peptide,GLP,that,enhances,insulin,secretion,pancreatic,cell,proliferation,making,therapeutic,target,type,diabetes,Although,crystal,structure,has,been,determined,its,function,mechanism,largely,unknown,Here,we,examined,biochemical,properties,sporadic,human,mutations,distal,from,site,among,which,dimerization,causes,loss,enzymatic,molecular,dynamics,simulations,revealed,induces,local,conformational,collapse,loop,residues,defined,open,closed,transitions,whereby,capping,active,are,involved,Further,directed,mutagenesis,guided,theoretical,predictions,verified,importance,Therefore,current,studies,combined,modeling,experimental,identification,provide,important,insights,into,biological,allow,evaluation,genetic,before,initiating,clinical,applications,drug,development
AB值：
0.578938
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