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
瘦瘦乌龟发布了新的文献求助10
刚刚
JL完成签到,获得积分10
1秒前
1秒前
充电宝应助PANYIAO采纳,获得10
2秒前
李木子完成签到,获得积分10
2秒前
sy发布了新的文献求助30
2秒前
彭于彦祖应助活力小虾米采纳,获得50
2秒前
雪晴完成签到,获得积分10
3秒前
4秒前
Edison完成签到,获得积分10
4秒前
锂能源完成签到,获得积分10
4秒前
香烟小厨发布了新的文献求助10
4秒前
潇洒的怜阳完成签到,获得积分10
4秒前
5秒前
6秒前
ananan完成签到,获得积分10
6秒前
田様应助李丹采纳,获得10
7秒前
sleepy发布了新的文献求助30
7秒前
Ammon应助Leon采纳,获得10
7秒前
FLZLC发布了新的文献求助10
9秒前
大个应助聪明的天亦采纳,获得10
9秒前
文子发布了新的文献求助10
10秒前
由富发布了新的文献求助10
10秒前
脑洞疼应助bodhi采纳,获得10
10秒前
华仔应助chruse采纳,获得10
10秒前
11秒前
淡淡菀给luan的求助进行了留言
13秒前
魔幻的翠容完成签到 ,获得积分10
13秒前
胡子木完成签到,获得积分10
15秒前
15秒前
科研通AI2S应助卟啉光环采纳,获得10
15秒前
852应助刘兆彬采纳,获得50
15秒前
16秒前
16秒前
16秒前
huangxiaoniu完成签到,获得积分10
16秒前
乐乐应助zfd采纳,获得10
16秒前
16秒前
仁爱宛筠完成签到,获得积分10
17秒前
orixero应助EricShen采纳,获得10
17秒前
高分求助中
Spray / Wall-interaction Modelling by Dimensionless Data Analysis 2000
ALA生合成不全マウスでの糖代謝異常の分子機構解析 520
Mathematics and Finite Element Discretizations of Incompressible Navier—Stokes Flows 500
2024 Medicinal Chemistry Reviews 400
Dictionary of socialism 350
Geochemistry, 2nd Edition 地球化学经典教科书第二版 300
Idoxuridine 260
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 3194019
求助须知:如何正确求助?哪些是违规求助? 2842911
关于积分的说明 8042344
捐赠科研通 2507365
什么是DOI,文献DOI怎么找? 1339774
科研通“疑难数据库(出版商)”最低求助积分说明 638807
邀请新用户注册赠送积分活动 607647