Elucidating the structural determinants of odor specificity in insect olfactory receptors

阐明昆虫嗅觉受体气味特异性的结构决定因素

• 批准号: 10625478
• 负责人: Josefina Inés Del Marmol
• 金额: $ 24.9万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-05 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625478
• 关键词: Address; Advisory Committees; Aedes; Affect; Alleles; Amino Acid Receptors; Amino Acid Sequence; Animals; Appointment; Behavioral Assay; Binding; Biochemical; Biological Assay; Biophysics; Chemicals; Complement; Complex; Computer Models; Cryoelectron Microscopy; Culicidae; Data; Dengue Fever; Detection; Development; Development Plans; Discrimination; Disease; Drosophila genus; Drosophila melanogaster; Electrophysiology (science); Elements; Endowment; Engineering; Environment; Exhibits; Family; Foundations; Functional Imaging; Genetic; Genetic Polymorphism; Goals; Human; Impairment; In Vitro; Insect Repellents; Insecta; Leadership; Ligand Binding; Ligands; Light; Link; Logic; Malaria; Mammals; Manuscripts; Mentors; Mentorship; Modality; Molecular; Mutagenesis; Mutation; Neurons; Odorant Receptors; Odors; Olfactory Pathways; Persons; Phase; Positioning Attribute; Preparation; Property; Research; Research Project Grants; Resolution; Resources; Ruta; Sensory; Smell Perception; Specificity; Structure; System; Technology; Testing; Training; Universities; Variant; Volatilization; Work; Yellow Fever; career development; combinatorial; drug discovery; flexibility; in vivo; insect disease vector; insight; molecular modeling; novel; olfactory receptor; olfactory stimulus; preference; prevent; programs; rational design; receptor; receptor binding; response; skills; small molecule; structural biology; structural determinants; tool; transmission process; zika fever

Project Summary The sense of smell provides animals with vital information about their environment. At the molecular level, olfactory stimuli consist of thousands of distinct small molecules that share no common chemical feature other than being volatile. To contend with this diversity, insects and mammals alike have evolved large families of olfactory receptors (ORs) that operate in a combinatorial way, whereby some receptors are broadly activated by many different odorants and others are exquisitely tuned to a specific compound. The molecular mechanisms that endow ORs with such diverse ligand-binding properties remain unknown, largely because the isolation and structural characterization of ORs has been a decades-long technological challenge. Using cryo-electron microscopy, I recently determined the first atomic-resolution structure of an insect OR bound to an odor. By determining the structures of additional insect ORs with broad and specific ligand-binding properties, the proposed research project will elucidate the molecular mechanism of odor detection and discrimination. To this end, the K99 mentored phase (Aim 1) will reveal the atomic structures of two primitive insect ORs with different ligand specificities unbound and in complex with multiple odor ligands, shedding light on the molecular determinants that underlie broad or specific odor selectivity. Next, the R00 independent phase (Aim 2) will focus on ORs from disease-carrying mosquitoes that participate in human host-seeking. These ORs exhibit small polymorphisms that drastically affect their ability to detect human odors. Elucidation of the atomic structure of these mosquito ORs bound to human volatiles will illuminate the molecular properties that enable mosquitoes to detect and prey on humans. Together, this research program will lend fundamental insight into the normal function of sensory processing of olfactory information. Additionally, as insect ORs are critically involved in human host-seeking that facilitates the spread of insect-borne diseases, this work will provide a foundation for the development of novel insect repellents that could curb diseases such as malaria, Zika, and dengue fever. The proposed development plan complements my training in structural biology and biophysics with computational modeling of receptor-ligand interactions and in vivo assays in Drosophila. At the end of the mentored phase, I will be equipped with the necessary tools to conduct comprehensive structural and functional studies of odor detection and discrimination by insect vectors of disease. To achieve these goals, I will take advantage of the extensive resources of the Rockefeller University, the mentorship of Dr. Vanessa Ruta and the appointment of an Advisory Committee that will lend expertise in key aspects of the project and career development. Additionally, with the support and resources from the MOSAIC/UE5 network I will expand my mentorship and leadership skills to successfully transition to an independent position while continuing my ongoing efforts to enhance diversity in the biomedical workforce.

项目摘要 嗅觉为动物提供了有关其环境的重要信息。在分子水平上 嗅觉刺激由数千种不同的小分子组成，这些分子没有共同的化学特征其他 而不是波动。为了应对这种多样性，昆虫和哺乳动物都进化了 以组合方式运行的嗅觉受体（OR），某些受体被广泛激活 许多不同的气味和其他种类被精心调整为特定的化合物。分子机制 具有这种不同配体结合特性的赋予OR仍然未知，主要是因为隔离和 ORS的结构表征一直是数十年的技术挑战。使用冷冻电子 显微镜，我最近确定了昆虫或与气味结合的第一个原子分辨率结构。经过 确定具有宽阔而特异的配体结合特性的其他昆虫的结构， 拟议的研究项目将阐明气味检测和歧视的分子机制。 为此，K99指导阶段（AIM 1）将揭示两种原始昆虫OR的原子结构 不同的配体特异性未结合，并具有多种气味配体，从而散发出分子的光 基于广泛或特定气味选择性的决定因素。接下来，R00独立阶段（AIM 2）将重点 从参与人类寻求宿主的伴侣蚊子的OR上。这些OR显示很小 多态性会严重影响其检测人类气味的能力。阐明原子结构 这些与人挥发物结合的蚊子会照亮使蚊子能够到达的分子特性 检测和猎物对人类。该研究计划将共同洞悉正常 嗅觉信息的感觉处理功能。另外，由于昆虫的OR与 寻求促进昆虫传播疾病传播的寻求人类的宿主，这项工作将为 可能抑制疟疾，寨卡病毒和登革热等新型驱虫剂的发展。 拟议的开发计划补充了我在结构生物学和生物物理学方面的培训 果蝇中受体配体相互作用和体内测定的计算模型。在 指导阶段，我将配备进行全面结构和功能的必要工具 疾病昆虫媒介的气味检测和歧视研究。为了实现这些目标，我将采取 洛克菲勒大学的广泛资源，Vanessa Ruta博士的指导和 任命一个咨询委员会，该委员会将在项目和职业的关键方面提供专业知识 发展。此外，借助Mosaic/UE5网络的支持和资源，我将扩展我的 指导和领导技能成功地过渡到独立职位，同时继续我的 正在进行的努力来增强生物医学劳动力的多样性。