Activation and Regulation Mechanisms of cGMP-dependent Protein Kinase I and II

cGMP依赖性蛋白激酶I和II的激活和调节机制

基本信息

批准号：
9506783
负责人：
Choel Woong Kim
金额：
$ 35.41万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9506783
关键词：
Acute Address Allosteric Regulation Amino Acids Aortic Aneurysm Binding Binding Proteins Binding Sites Biochemical Blood Vessels Bone Growth C-terminal Cardiovascular Diseases Cells Complex Crystallization Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic GMP Cyclic Nucleotides Cystic Fibrosis Data Disease Dissection Drug Targeting Erectile dysfunction Functional disorder Goals Grant Guanylate Cyclase Heart failure Human Hypertension Individual Learning Length Leucine Zippers Libraries Lung diseases Measurement Mediating Mediator of activation protein Membrane Memory Memory Loss Molecular Molecular Conformation Muscle Tonus Mutate N-terminal Neurologic Nitrates Nitric Oxide Nociception Osteoporosis Pathway interactions Patients Pharmaceutical Preparations Pharmacology Pharmacotherapy Phosphodiesterase Inhibitors Phosphotransferases Platelet aggregation Protein Binding Domain Protein Isoforms Protein Kinase Protein Kinase Interaction Proteins Pulmonary Hypertension Regulation Renin Resolution Roentgen Rays Role Safety Signal Pathway Signal Transduction Smooth Muscle Specificity Structure Surface Tertiary Protein Structure Testing Therapeutic Thoracic Aortic Aneurysm Time Tissues analog biophysical techniques cGMP-dependent protein kinase I cyclic GMP-binding protein design dimer inhibitor/antagonist innovation monomer protein activation protein structure public health relevance therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The specific aims of this proposal are to obtain high-resolution structures of the cGMP- binding domains of cGMP-dependent protein kinase I and II (PKGs) and to use the structural information to design activators specific for PKGs. As key receptors for cGMP, PKG I and II mediate most effects of cGMP-elevating drugs such as nitric oxide-releasing agents for the treatment of many hypertensive diseases and phosphodiesterase inhibitors for the treatment of erectile dysfunction. While PKG I and II are therapeutic targets fo treating hypertensive diseases such as arterial and pulmonary hypertension, heart failure, erectile dysfunction and osteoporosis, developing specific activators has been difficult mainly due to a lack of available structural information. To obtain structural information needed for developing specific activators of PKG I and II, our group recently determined crystal structures of a fragment of the regulatory domains of human PKG I and II that specifically bind cGMP and activate catalytic activity. My long-term goals are to understand the activation mechanism of PKG mediated by cGMP and to develop specific activators of PKG that can be used for treating hypertensive diseases. To achieve these goals, my plans are to understand the role of the non-selective A-domain in activation of PKG I, to understand the cyclic nucleotide selectivity mechanism of PKG II, to screen known cGMP analogs for isoform specific binding and activation, and determine their co-crystal structures and use the resulting structural information for developing isoform specific activators of PKG I and II.

描述（由适用提供）：该建议的具体目的是获得CGMP依赖性蛋白激酶I和II（PKG）的CGMP结合域的高分辨率结构，并使用结构信息来设计特定于PKGS的激活剂。作为CGMP的关键受体，PKG I和II介导了CGMP高度鉴定药物的大多数作用，例如一氧化氮释放剂，用于治疗许多高血压疾病和磷酸二酯酶抑制剂，以治疗勃起功能障碍。尽管PKG I和II是治疗高血压疾病（例如手术，心力衰竭，勃起功能障碍和骨质疏松症）的治疗靶标，但由于缺乏可用的结构信息，开发特定的激活剂很困难。为了获得开发PKG I和II的特定活化剂所需的结构信息，我们的小组最近确定了人类PKG I和II的调节域的片段的晶体结构，该片段专门结合CGMP并激活催化活性。我的长期目标是了解CGMP介导的PKG的激活机制，并开发可用于治疗高血压疾病的PKG的特定活化剂。为了实现这些目标，我的计划是了解非选择性A域在激活PKG I中的作用，以了解PKG II的环状核苷酸选择性机制，以筛选已知的同型特异性结合和激活的CGMP类似物，并确定其共和性结构并确定其共结构信息并将其用于生成的结构信息来开发同型的特定于II pkg ii ii ii ii ii ii ii ii ii i II ii i II ii i II ii i II i II和pk i II和pk i II。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Switching Cyclic Nucleotide-Selective Activation of Cyclic Adenosine Monophosphate-Dependent Protein Kinase Holoenzyme Reveals Distinct Roles of Tandem Cyclic Nucleotide-Binding Domains.

环状单磷酸腺苷依赖性蛋白激酶全酶的环状核苷酸选择性激活的切换揭示了串联环状核苷酸结合域的独特作用。

DOI：
10.1021/acschembio.7b00732
发表时间：
2017
期刊：
ACS chemical biology
影响因子：
4
作者：
He,Daniel;Lorenz,Robin;Kim,Choel;Herberg,FriedrichW;Lim,ChintenJames
通讯作者：
Lim,ChintenJames

Cyclic nucleotide selectivity of protein kinase G isozymes.

蛋白激酶 G 同工酶的环核苷酸选择性。

DOI：
10.1002/pro.4008
发表时间：
2021
期刊：
Protein science : a publication of the Protein Society
影响因子：
0
作者：
Kim,Choel;Sharma,Rajesh
通讯作者：
Sharma,Rajesh

Structures of cGMP-Dependent Protein Kinase (PKG) Iα Leucine Zippers Reveal an Interchain Disulfide Bond Important for Dimer Stability.

cGMP 依赖性蛋白激酶 (PKG) Iα 亮氨酸拉链的结构揭示了对二聚体稳定性很重要的链间二硫键。

DOI：
10.1021/acs.biochem.5b00572
发表时间：
2015
期刊：
Biochemistry
影响因子：
2.9
作者：
Qin,Liying;Reger,AlbertS;Guo,Elaine;Yang,MatthewP;Zwart,Peter;Casteel,DarrenE;Kim,Choel
通讯作者：
Kim,Choel

Mechanism of cAMP Partial Agonism in Protein Kinase G (PKG).

蛋白激酶 G (PKG) 中 cAMP 部分激动的机制。

DOI：
10.1074/jbc.m115.685305
发表时间：
2015
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
VanSchouwen,Bryan;Selvaratnam,Rajeevan;Giri,Rajanish;Lorenz,Robin;Herberg,FriedrichW;Kim,Choel;Melacini,Giuseppe
通讯作者：
Melacini,Giuseppe

Generation of candidate ligands for nicotinic acetylcholine receptors via in situ click chemistry with a soluble acetylcholine binding protein template.

DOI：
10.1021/ja3001858
发表时间：
2012-04-18
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
影响因子：
15
作者：
Grimster, Neil P.;Stump, Bernhard;Fotsing, Joseph R.;Weide, Timo;Talley, Todd T.;Yamauchi, John G.;Nemecz, Akos;Kim, Choel;Ho, Kwok-Yiu;Sharpless, K. Barry;Taylor, Palmer;Fokin, Valery V.
通讯作者：
Fokin, Valery V.