Molecular Dynamic Investigations of the Mutational Effects on Structural Characteristics and Tunnel Geometry in CYP17A1

CYP17A1型 分子动力学 化学 突变 分子模型 生物物理学 突变体 生物 立体化学 计算化学 生物化学 基因
作者
Yinglu Cui,Qing-Chuan Zheng,Ji-Long Zhang,Qiao Xue,Yan Wang,Hong-Xing Zhang
出处
期刊:Journal of Chemical Information and Modeling [American Chemical Society]
被引量:33
标识
DOI:10.1021/ci400553w
摘要

Cytochrome P450 (CYP) 17A1 is a dual-function monooxygenase with a critical role in the synthesis of many human steroid hormones. The enzyme is an important target for the treatment of breast and prostate cancers that proliferate in response to estrogens and androgens. Despite the ample experimental mutagenesis data, the molecular origin and the structural motifs for the enzymatic activities deficiencies have not been rationalized at the atomic resolution. To this end, we have investigated the effects on structural characteristics and tunnel geometry upon single point mutations in CYP17A1. The MD simulation results combined with PMF calculations and MM-GBSA calculations render an "access mechanism" which encapsulates the effects of mutations on the changes in both structural flexibility and tunnel dynamics, bridging the gap between the theory and the experimentally observed results of enzymatic activity decrease. The underlying molecular mechanism of the heterogeneities in open/closed conformational changes, as well as the wider opening of their respective major tunnels between wt17A1 and two mutants, may be attributed to the closer distances of hydrophobic residues or the disruption of a hydrophobic core. The knowledge of ligand binding characteristics and key residues contributions could guide future experimental and computational work on CYPs so that desirable changes in their enzymatic activities may be achieved. The present study provides important insights into the structure-function relationships of CYP17A1 protein, which could contribute to further understanding about 17-hydroxylase deficiencies and may also improve the understanding of polycystic ovary disease.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
nan发布了新的文献求助10
3秒前
kevin1018完成签到,获得积分10
3秒前
安详的大象完成签到,获得积分10
4秒前
闪闪冰淇淋完成签到,获得积分10
5秒前
林澈发布了新的文献求助10
6秒前
香蕉觅云应助小马2023采纳,获得10
7秒前
8秒前
9秒前
9秒前
彭于晏应助安详寒蕾采纳,获得10
9秒前
cruise发布了新的文献求助10
10秒前
zhiyuan完成签到,获得积分10
11秒前
Summer完成签到,获得积分10
12秒前
ZXW发布了新的文献求助10
13秒前
14秒前
高大的网络完成签到,获得积分10
14秒前
15秒前
15秒前
15秒前
南音发布了新的文献求助10
16秒前
大模型应助暴躁小兔采纳,获得10
16秒前
16秒前
18秒前
18秒前
畅畅发布了新的文献求助10
19秒前
orixero应助Atopos采纳,获得10
20秒前
20秒前
YY-Bubble完成签到,获得积分10
21秒前
迷路以蓝完成签到,获得积分10
21秒前
Ming完成签到,获得积分10
22秒前
打工羊发布了新的文献求助10
23秒前
光亮天抒发布了新的文献求助10
23秒前
lily发布了新的文献求助10
23秒前
24秒前
火日立完成签到,获得积分20
24秒前
wcy发布了新的文献求助10
25秒前
cruise完成签到,获得积分10
26秒前
28秒前
28秒前
ding1126关注了科研通微信公众号
28秒前
高分求助中
Spray / Wall-interaction Modelling by Dimensionless Data Analysis 2000
Evolution 3rd edition 1500
保险藏宝图 1000
Lire en communiste 1000
Mantiden: Faszinierende Lauerjäger Faszinierende Lauerjäger 700
PraxisRatgeber: Mantiden: Faszinierende Lauerjäger 700
Mathematics and Finite Element Discretizations of Incompressible Navier—Stokes Flows 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3185969
求助须知:如何正确求助?哪些是违规求助? 2836319
关于积分的说明 8008478
捐赠科研通 2498682
什么是DOI,文献DOI怎么找? 1333763
科研通“疑难数据库(出版商)”最低求助积分说明 636912
邀请新用户注册赠送积分活动 604742