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: 10191177
• 负责人: Josefina Inés Del Marmol
• 金额: $ 13.31万
• 依托单位: ROCKEFELLER UNIVERSITY
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10191177
• 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; 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; Phase; Positioning Attribute; Preparation; Property; Research; Research Project Grants; Resolution; Resources; Ruta; Sensory; Smell Perception; Specificity; Structure; System; Testing; Training; Universities; Variant; Work; Yellow Fever; career development; combinatorial; design; drug discovery; flexibility; in vivo; insect disease vector; insight; molecular modeling; novel; olfactory receptor; olfactory stimulus; preference; prevent; programs; receptor; receptor binding; response; skills; small molecule; structural biology; tool; 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， 嗅觉刺激物由数千种不同的小分子组成，这些小分子没有共同的化学特征， 而不是反复无常为了应对这种多样性，昆虫和哺乳动物都进化出了大家族， 嗅觉受体（OR）以组合方式工作，其中一些受体被广泛激活， 许多不同的气味剂和其他的被精细地调整到特定的化合物。的分子机制 赋予OR如此多样的配体结合特性的机制仍然是未知的，主要是因为分离和 OR的结构表征是一个长达数十年的技术挑战。使用低温电子 在显微镜下，我最近确定了第一个原子分辨率结构的昆虫或绑定到气味。通过 确定具有广泛和特异性配体结合特性的其他昆虫OR的结构， 建议的研究项目将阐明气味探测和辨别的分子机制。 为此，K99指导阶段（目标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，并与多种气味配体复合， 决定因素的基础广泛或具体的气味选择性。接下来，R 00独立阶段（目标2）将重点关注 来自参与人类宿主寻找的携带疾病的蚊子的OR。这些手术室表现出小 基因多态性极大地影响了它们检测人类气味的能力。原子结构解析 这些与人类挥发物结合的蚊子OR将阐明使蚊子能够 侦测并捕食人类总之，这项研究计划将提供基本的洞察力， 嗅觉信息的感觉处理功能。此外，由于昆虫OR与 人类寻找宿主，促进虫媒疾病的传播，这项工作将提供一个基础， 开发新型驱虫剂，可以遏制疟疾、寨卡和登革热等疾病。 拟议的发展计划补充了我在结构生物学和生物物理学方面的培训， 受体-配体相互作用的计算建模和果蝇体内测定。结束时 在辅导阶段，我将配备必要的工具，进行全面的结构和功能 研究疾病媒介昆虫的气味检测和区分。为了实现这些目标，我将 洛克菲勒大学的广泛资源，博士的指导优势。 任命一个咨询委员会，在项目和职业生涯的关键方面提供专业知识 发展此外，在MOSAIC/UE 5网络的支持和资源下，我将扩大我的 指导和领导技能，成功过渡到一个独立的位置，同时继续我的 不断努力提高生物医学劳动力的多样性。