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
lbyscu完成签到 ,获得积分10
1秒前
1秒前
4秒前
湖里发布了新的文献求助10
5秒前
7秒前
8秒前
斯文败类应助湖里采纳,获得10
10秒前
10秒前
12秒前
呼呼呼发布了新的文献求助10
12秒前
Billy应助独特靖巧采纳,获得10
12秒前
yfy完成签到 ,获得积分10
13秒前
杨tong完成签到 ,获得积分10
14秒前
XiheNiu完成签到,获得积分20
14秒前
orixero应助深情映冬采纳,获得10
15秒前
不配.应助wlei采纳,获得10
15秒前
阔达的书文关注了科研通微信公众号
16秒前
xuerkk发布了新的文献求助10
17秒前
17秒前
17秒前
XiheNiu发布了新的文献求助10
17秒前
20秒前
maxinghrr完成签到,获得积分0
20秒前
21秒前
22秒前
23秒前
25秒前
ZhengYingqi发布了新的文献求助10
25秒前
26秒前
深情映冬发布了新的文献求助10
28秒前
29秒前
31秒前
挡住所有坏运气888完成签到,获得积分10
31秒前
32秒前
顾矜应助狂野的绿柏采纳,获得10
32秒前
霍曼完成签到,获得积分10
33秒前
深情映冬完成签到,获得积分10
34秒前
Ail完成签到,获得积分10
34秒前
wang发布了新的文献求助10
35秒前
KK完成签到,获得积分10
35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
安全防范技术与工程 500
Mathematics and Finite Element Discretizations of Incompressible Navier—Stokes Flows 500
2-Acetyl-1-pyrroline: an important aroma component of cooked rice 500
A real-time energy management strategy based on fuzzy control and ECMS for PHEVs 400
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 3190618
求助须知:如何正确求助?哪些是违规求助? 2839902
关于积分的说明 8025837
捐赠科研通 2502907
什么是DOI,文献DOI怎么找? 1336666
科研通“疑难数据库(出版商)”最低求助积分说明 637915
邀请新用户注册赠送积分活动 606166