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

• 批准号: 9102231
• 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
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9102231
• 关键词: Acute; Address; Allosteric Regulation; Amino Acids; Binding; Binding Sites; Biochemical; Blood Vessels; Bone Growth; C-terminal; Cardiovascular Diseases; Cells; Complex; 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; Health; Heart failure; Human; Hypertension; Individual; Learning; Length; Leucine Zippers; Libraries; Lung diseases; Measurement; Mediating; Mediator of activation protein; Membrane; Memory; Memory Loss; Molecular; Muscle Tonus; Mutate; N-terminal; Neurologic; Nitrates; Nitric Oxide; Nociception; Osteoporosis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phosphodiesterase Inhibitors; Phosphotransferases; Platelet aggregation; Protein Isoforms; Proteins; Regulation; Renin; Resolution; Roentgen Rays; Role; Safety; Signal Pathway; Signal Transduction; Smooth Muscle; Specificity; Structure; Surface; Testing; Therapeutic; Thoracic Aortic Aneurysm; Time; Tissues; analog; base; biophysical techniques; cGMP-dependent protein kinase I; cyclic GMP-binding protein; design; dimer; inhibitor/antagonist; innovation; monomer; pulmonary arterial hypertension; therapeutic target

 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（由申请人提供）：本提案的具体目的是获得 cGMP 依赖性蛋白激酶 I 和 II (PKG) 的 cGMP 结合域的高分辨率结构，并使用结构信息设计针对 PKG 的特异性激活剂。作为 cGMP 的关键受体，PKG I 和 II 介导 cGMP 升高药物的大部分作用，例如用于治疗许多高血压疾病的一氧化氮释放剂和用于治疗勃起功能障碍的磷酸二酯酶抑制剂。虽然 PKG I 和 II 是治疗高血压疾病（如动脉和肺动脉高压、心力衰竭、勃起功能障碍和骨质疏松症）的治疗靶点，但开发特异性激活剂一直很困难，主要是由于缺乏可用的结构信息。为了获得开发 PKG I 和 II 特异性激活剂所需的结构信息，我们小组最近确定了人 PKG I 和 II 调节域片段的晶体结构，该片段特异性结合 cGMP 并激活催化活性。我的长期目标是了解cGMP介导的PKG激活机制，并开发可用于治疗高血压疾病的特异性PKG激活剂。为了实现这些目标，我的计划是了解非选择性 A 结构域在 PKG I 激活中的作用，了解 PKG II 的环核苷酸选择性机制，筛选已知的 cGMP 类似物的异构体特异性结合和激活，确定它们的共晶结构，并使用所得的结构信息来开发 PKG I 和 II 的异构体特异性激活剂。