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
Peng完成签到 ,获得积分10
1秒前
redstone发布了新的文献求助10
1秒前
luoxiaotu198完成签到,获得积分10
1秒前
xxx发布了新的文献求助10
1秒前
123发布了新的文献求助10
2秒前
朴素涵雁发布了新的文献求助10
2秒前
amnesiamber发布了新的文献求助10
2秒前
西洲发布了新的文献求助10
3秒前
zz完成签到,获得积分10
3秒前
独立江湖女完成签到 ,获得积分10
3秒前
玩命的小翠完成签到 ,获得积分10
3秒前
温暖天与发布了新的文献求助10
4秒前
XY应助我真的行采纳,获得10
4秒前
wang发布了新的文献求助10
5秒前
需要交流的铅笔完成签到 ,获得积分10
5秒前
gaigai完成签到,获得积分10
5秒前
内向翰完成签到,获得积分10
5秒前
廖骏完成签到,获得积分10
6秒前
orixero应助生米A吴采纳,获得10
6秒前
6秒前
maox1aoxin应助猪猪采纳,获得30
7秒前
duolaAmeng完成签到,获得积分10
7秒前
鱿鱼阿章完成签到,获得积分10
7秒前
呆瓜完成签到,获得积分10
7秒前
现代雪晴完成签到,获得积分10
8秒前
9秒前
酷波er应助LIN采纳,获得10
9秒前
隐形曼青应助波鲁鲁采纳,获得10
9秒前
ffff完成签到,获得积分10
9秒前
lz关闭了lz文献求助
9秒前
10秒前
rsy完成签到,获得积分10
10秒前
锂炸完成签到,获得积分10
10秒前
小蘑菇应助西洲采纳,获得10
11秒前
DH完成签到 ,获得积分10
11秒前
led完成签到,获得积分10
11秒前
cheng发布了新的文献求助10
12秒前
爆米花应助许诺采纳,获得10
12秒前
13秒前
SICHEN完成签到,获得积分10
13秒前
高分求助中
Write Like a Chemist: A Guide and Resource (第二版) 600
Mixed-anion Compounds 600
Language injustice and social equity in EMI policies in China 500
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
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 3201358
求助须知:如何正确求助?哪些是违规求助? 2850920
关于积分的说明 8075448
捐赠科研通 2514852
什么是DOI,文献DOI怎么找? 1347501
科研通“疑难数据库(出版商)”最低求助积分说明 640446
邀请新用户注册赠送积分活动 610650