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
早早入眠完成签到,获得积分10
刚刚
木南大宝完成签到 ,获得积分10
刚刚
1秒前
2秒前
机灵盼芙完成签到 ,获得积分10
2秒前
明理友琴完成签到,获得积分10
2秒前
2秒前
小二郎应助Ophelia采纳,获得10
2秒前
芒果味完成签到 ,获得积分10
3秒前
5秒前
明理友琴发布了新的文献求助10
6秒前
兜兜发布了新的文献求助10
7秒前
苗冬发布了新的文献求助10
9秒前
杳鸢应助jjjdy采纳,获得30
10秒前
虚心的爆米花完成签到,获得积分10
10秒前
江上清风游完成签到,获得积分10
11秒前
Ella完成签到,获得积分10
11秒前
不倒翁37完成签到,获得积分10
12秒前
李健应助露露采纳,获得10
12秒前
咪吖完成签到 ,获得积分10
18秒前
18秒前
zwy完成签到 ,获得积分10
19秒前
传奇3应助pine采纳,获得10
19秒前
Forizix发布了新的文献求助30
23秒前
一路狂奔等不了完成签到 ,获得积分10
26秒前
共享精神应助欣喜的秋灵采纳,获得30
27秒前
NexusExplorer应助科研通管家采纳,获得10
30秒前
深情安青应助科研通管家采纳,获得10
30秒前
脑洞疼应助科研通管家采纳,获得10
30秒前
爆米花应助科研通管家采纳,获得10
30秒前
乐乐应助科研通管家采纳,获得10
30秒前
NexusExplorer应助科研通管家采纳,获得10
30秒前
大个应助科研通管家采纳,获得10
30秒前
30秒前
丹霞应助科研通管家采纳,获得10
30秒前
CipherSage应助jyd采纳,获得10
31秒前
R9an发布了新的文献求助10
31秒前
夏xia完成签到 ,获得积分10
32秒前
伴佰发布了新的文献求助10
33秒前
RMQ2025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
Evolution 3rd edition 1500
Mantiden: Faszinierende Lauerjäger Faszinierende Lauerjäger 700
PraxisRatgeber: Mantiden: Faszinierende Lauerjäger 700
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
A new species of Coccus (Homoptera: Coccoidea) from Malawi 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 3187734
求助须知:如何正确求助?哪些是违规求助? 2837488
关于积分的说明 8015060
捐赠科研通 2500112
什么是DOI,文献DOI怎么找? 1334764
科研通“疑难数据库(出版商)”最低求助积分说明 637271
邀请新用户注册赠送积分活动 605251