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
季不住完成签到,获得积分10
刚刚
刚刚
文艺的青旋完成签到 ,获得积分10
1秒前
呆萌的土豆完成签到,获得积分10
1秒前
3秒前
橘子橘子完成签到 ,获得积分10
3秒前
你香完成签到,获得积分10
3秒前
midoli发布了新的文献求助10
3秒前
tinysweet发布了新的文献求助100
5秒前
跟往事扯淡完成签到,获得积分10
5秒前
6秒前
8秒前
9秒前
英姑应助2021采纳,获得10
9秒前
volition完成签到 ,获得积分10
10秒前
橘子完成签到,获得积分10
10秒前
不安青牛应助Jiangnj采纳,获得10
13秒前
13秒前
Henry发布了新的文献求助10
13秒前
qq发布了新的文献求助10
14秒前
dd发布了新的文献求助10
14秒前
aaa完成签到,获得积分10
15秒前
15秒前
16秒前
16秒前
17秒前
所所应助称心胡萝卜采纳,获得10
17秒前
dushicheng发布了新的文献求助10
17秒前
Lucas应助周小花采纳,获得10
19秒前
19秒前
科研通AI2S应助忧伤的书易采纳,获得10
20秒前
20秒前
小丹丹发布了新的文献求助10
20秒前
斯文百招完成签到 ,获得积分10
21秒前
舒适丹雪发布了新的文献求助10
21秒前
qq完成签到,获得积分20
22秒前
23秒前
峥2发布了新的文献求助10
23秒前
哲学带带师完成签到,获得积分10
28秒前
祈愿完成签到 ,获得积分10
28秒前
高分求助中
Spray / Wall-interaction Modelling by Dimensionless Data Analysis 2000
Mixed-anion Compounds 600
A new species of Velataspis (Hemiptera Coccoidea Diaspididae) from tea in Assam 500
Earth System Geophysics 500
Aspects of Babylonian celestial divination: the lunar eclipse tablets of Enūma Anu Enlil 500
Geochemistry, 2nd Edition 地球化学经典教科书第二版 401
2024 Medicinal Chemistry Reviews 400
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 3200187
求助须知:如何正确求助?哪些是违规求助? 2849924
关于积分的说明 8070476
捐赠科研通 2513771
什么是DOI,文献DOI怎么找? 1346598
科研通“疑难数据库(出版商)”最低求助积分说明 640229
邀请新用户注册赠送积分活动 610181