Mechanisms of chemosensory recognition

摘要 嗅觉系统编码和分析气味。化学物质与受体大家族的成员结合 具有不同化学特征的蛋白质。虽然我们有一个全面的受体基因清单， 这是嗅觉检测的基础，我们还远没有对嗅觉检测有类似的全面了解。 嗅觉系统检测到的化学特征。 这项提议利用了四项发展-记录整个嗅觉输出的能力 犁鼻系统（vomeronasal system）是一个庞大的、结构刚性的气味物质（硫酸化的、羧基化的和 葡萄糖醛酸化类固醇），一种鉴定具有特定配体检测的受体基因的新工具 和一种用于异位表达所选受体基因并研究其功能的新工具， 开发第一个系统范围内的嗅觉系统如何代表化学世界的理解。的 总体目标是发展类似于（和类似的预测能力）锥的作用的见解 光感受器调谐曲线在我们对色觉的理解中。 该提案的具体目标是：（1）通过一个新的组合编码原理， 通过一个大的配体对犁鼻系统的覆盖、冗余和特异性进行全系统分析 筛选和定量分析激活每种受体所需的结构特征;和（2） 揭示受体序列和气味结构之间的关系，通过去乙酰化一个大的亚家族， 犁鼻受体基因初步数据表明类固醇代谢物的结构刚性 大大有助于这些目标的可追踪性，支持定量和预测分析， 全系统规模。

ABSTRACT The olfactory system encodes and analyzes odorants. Chemicals bind to members of large families of receptor proteins tuned to different chemical features. While we have a comprehensive inventory of the receptor genes that underlie olfactory detection, we are far from having a similarly comprehensive understanding of the chemical features detected by olfactory systems. This proposal leverages four developments—the ability to record the output of an entire olfactory system (the vomeronasal system), a large and structurally-rigid class of odorants (sulfated, carboxylated, and glucuronidated steroids), a new tool to identify the receptor gene(s) that have particular ligand detection profiles, and a new tool for ectopically expressing a chosen receptor gene and studying its function—to develop the first system-wide understanding of how an olfactory system represents the chemical world. The overarching goal is to develop insights analogous to (and with similar predictive power to) the role of cone photoreceptor tuning curves in our understanding of color vision. The specific aims of the proposal are (1) to reveal new principles of combinatorial coding through a system-wide analysis of the vomeronasal system’s coverage, redundancy, and specificity via a large ligand screen and quantitative analysis of the structural features required for activating each receptor; and (2) to reveal relationships between receptor sequence and odorant structure by deorphanizing a large subfamily of vomeronasal receptor genes. Preliminary data suggest that structural rigidity of steroid metabolites contributes greatly to the tractability of these aims, supporting quantitative and predictive analysis on a system-wide scale.