Structural Insights to Insulin Receptor Ligand Interactions

胰岛素受体配体相互作用的结构见解

基本信息

批准号：
10367480
负责人：
CHRISTOPHER P. HILL
金额：
$ 39.71万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-25 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10367480
关键词：
Acute Address Allosteric Site Animals Binding Biochemical Biological C-terminal Cessation of life Chronic Clinical Cold Chains Complement Complex Cone Cryoelectron Microscopy DNA Data Development Diabetes Mellitus Disulfides Engineering Fishes Future Glucose Goals Growth Health Hyperglycemia Hypoglycemia Immobilization Insulin Insulin Infusion Systems Insulin Receptor Insulin Resistance Insulin, Lispro, Human Lead Length Ligands Long-Acting Insulin Metabolic Control Metabolic Pathway Miniature Swine Molecular Molecular Conformation Mus Mutation Negative Staining Outcome Pathway interactions Patients Peptides Phage Display Physiological Property Proteins Pump Rattus Receptor Signaling Refrigeration Reporting Resistance Resolution Serum Signal Pathway Signal Transduction Snail Venoms Snails Structure Subcutaneous Injections Testing Therapeutic Transmembrane Domain Variant Venoms analog aptamer base blood glucose regulation design experience experimental study improved insight insulin dimers interest nanodisk next generation novel preclinical study prevent receptor receptor binding reconstruction response success therapeutically effective tumor growth type I diabetic

Acute Address Allosteric Site Animals Binding Biochemical Biological C-terminal Cessation of life Chronic Clinical Cold Chains Complement Complex Cone Cryoelectron Microscopy DNA Data Development Diabetes Mellitus Disulfides Engineering Fishes Future Glucose Goals Growth Health Hyperglycemia Hypoglycemia Immobilization Insulin Insulin Infusion Systems Insulin Receptor Insulin Resistance Insulin, Lispro, Human Lead Length Ligands Long-Acting Insulin Metabolic Control Metabolic Pathway Miniature Swine Molecular Molecular Conformation Mus Mutation Negative Staining Outcome Pathway interactions Patients Peptides Phage Display Physiological Property Proteins Pump Rattus Receptor Signaling Refrigeration Reporting Resistance Resolution Serum Signal Pathway Signal Transduction Snail Venoms Snails Structure Subcutaneous Injections Testing Therapeutic Transmembrane Domain Variant Venoms analog aptamer base blood glucose regulation design experience experimental study improved insight insulin dimers interest nanodisk next generation novel preclinical study prevent receptor receptor binding reconstruction response success therapeutically effective tumor growth type I diabetic

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项目摘要

ABSTRACT Insulin treatment dramatically improves the health of people with diabetes, and is usually administered as a daily long-acting insulin and a prandial fast-acting insulin. Despite considerable success, a number of important challenges remain, including three major limitations that are addressed in this proposal. First, even the best clinically-available fast-acting insulins are too slow and last too long to provide tight control of serum glucose within the physiological range, resulting in substantial excursions outside of this range and chronic hyperglycemia or acute hypoglycemic complications. Second, currently available insulins require continual refrigeration to avoid aggregation, whereas therapeutic insulins that do not require cold-chain delivery would offer considerable advantages, especially for use in long-term insulin pumps and in circumstances where electrical power is unreliable. Third, because insulin stimulates two signals, one therapeutically advantageous for metabolic control (Akt pathway) and one therapeutically concerning for mitogenic growth (Erk pathway), there is interest in developing analogs that preferentially stimulate the Akt pathway. This proposal takes a biochemical and structure-based approach to gain mechanistic insight to each of these concerns, including cryo-EM structure determination of receptor-ligand complexes complemented by a variety of approaches, including cell signaling and mouse glucose-responsiveness studies. Aim 1 focusses on two humanized variants of cone snail venom insulins, which lack residues that make native insulin dimeric and inherently slow acting upon subcutaneous injection, and have been engineered to provide fast response, short duration of action, and high potency. Aim 2 focusses on approaches to render insulins resistant to aggregation/fibrillation, including following up on the surprising finding that one of the humanized venom insulins is highly resistant to aggregation. Aim 3 explores the remarkable property of some receptor ligands to elicit biased signaling that emphasizes either the Akt or the Erk pathways, and offers potential to understand the structural basis for these effects. Completion of these aims will provide fundamental mechanistic insights and inform efforts to develop improved therapeutics.

抽象的胰岛素治疗极大地改善了糖尿病患者的健康长效胰岛素和奶油快速作用胰岛素。尽管取得了很大的成功，但许多重要仍然存在挑战，包括该提案中解决的三个主要限制。首先，即使是最好的临床上可用的快速作用胰岛素太慢，持续时间太长，无法对血清葡萄糖进行严格的控制在生理范围内，导致该范围以外的大量偏移和慢性高血糖或急性降血糖并发症。第二，当前可用的胰岛素需要持续的制冷以避免聚集，而不需要冷链交付的治疗性胰岛素将提供相当大的优势，特别是用于长期胰岛素泵和电力的情况不可靠。第三，因为胰岛素刺激两个信号，一种在治疗上对代谢控制有利（AKT途径）和一种有关有丝分裂生长（ERK途径）的治疗方法，对开发优先刺激AKT途径的类似物。该建议采用生化和基于结构的方法来获得对这些问题的机械洞察力，包括冷冻EM结构通过多种方法补充的受体配体复合物的确定，包括细胞信号和小鼠葡萄糖反应研究。目标1重点介绍两个人源化蜗牛毒液的变体胰岛素缺乏使天然胰岛素二聚体并固有地作用于皮下的残留物注射，并已设计为提供快速响应，短时间的作用和高效力。目标2 专注于使胰岛素具有抗聚合/纤颤的胰岛素的方法，包括跟进令人惊讶的是，人性化的毒液胰岛素之一对聚集具有很高的抵抗力。 AIM 3探索某些受体配体的显着特性引起了强调AKT或 ERK途径，并提供了了解这些影响的结构基础的潜力。这些目标的完成将提供基本的机械见解，并为开发改进的治疗剂提供努力。