Structural Studies and Drug Discovery Illuminate Serotonin Pharmacology

项目摘要/摘要 该实验室的主要目标是提供对5-羟色胺信号和功能的详细结构和功能洞察。 转运，并阐明药物和药物如何调节受体和转运体的功能。5羟色胺(5- 羟色胺(5-羟色胺，5-羟色胺)在中枢神经系统内外调节着许多人类生理，包括认知， 情绪、内分泌功能和心血管发育。然而，尽管5-羟色胺的生理和医学上 重要性，原子水平对5-羟色胺信号和运输机制的洞察，以及药物如何相互作用 有了这些分子靶点，在很大程度上仍然难以捉摸。这种缺乏理解导致了药物安全。 过去的问题，并极大地阻碍了探索许多5-羟色胺的新的治疗应用的靶点。 因此，我们的实验室专注于两个尚未得到充分研究的5-羟色胺靶标。实验室的第一个主要方向是 阐明5-HT1E受体的配体结合和激活，5-HT1E受体是人们最不了解的5-羟色胺受体，其 生理作用尚不清楚。与所有其他5-羟色胺受体不同，5-羟色胺受体没有选择性的化合物。 HT1ER，这提出了关于其结合口袋和 受体激活的机制。为了回答这些问题，我们将确定G的CryoEM结构 蛋白质偶联的5-HT1ER，这将提供对配体结合口袋的详细结构洞察 结构，以及受体的构象变化负责G蛋白的激活。第二大调 该项目的重点是囊泡单胺转运体2(VMAT2)，这是一种重要的储存和运输工具 神经递质信号的调节，以及从糖尿病到苯丙胺的各种疾病的靶点 虐待。尽管它具有生物学和医学意义，但对它在哪里和在哪里缺乏原子水平的洞察 底物、药物或药物如何结合，或它们如何调节VMAT2功能。因此，我们将 确定VMAT2与不同底物和药物结合的晶体结构，阐明基本原理 转运和药物调节的机制，并表征不同结合的精确结构 网站。我们将进一步将我们的分子洞察力用于基于结构的药物发现，以开发 用于VMAT2(病程)生物学体外研究的药理和化学新工具化合物 在活体内。我们的研究在技术和概念上都是创新的，因为 结构、药理和药物发现方法将提供一个前所未有的视角 两个被忽视和未被充分研究的5-羟色胺药物靶点的分子机制。

Project Summary/Abstract The main goal of the lab is to provide detailed structural and functional insight into serotonin signaling and transport, and elucidate how drugs and medications modulate receptor and transporter function. Serotonin (5- hydroxytryptamine, 5-HT) regulates much of human physiology in- and outside the CNS, including cognition, mood, endocrine function and cardiovascular development. However, despite 5-HT's physiological and medical importance, atomic-level insight into the mechanisms of 5-HT signaling and transport, and how drugs interact with these molecular targets, has remained largely elusive. This lack of understanding has led to drug safety issues in the past, and greatly hindered the exploration of many 5-HT targets for novel therapeutic applications. Our lab is thus focused on two grossly understudied 5-HT targets. The first major direction of the lab is to elucidate ligand binding and activation of the 5-HT1E receptor, the least understood 5-HT receptor whose physiological role is unknown. Unlike for all other 5-HT receptors, there are no selective compounds for 5- HT1ER, which raises important questions about the molecular architecture of its binding pocket and mechanisms of receptor activation. To answer these questions, we will determine the cryoEM structure of G protein-coupled 5-HT1ER, which will provide detailed structural insight into the ligand binding pocket architecture, and the receptor's conformational changes responsible for G protein activation. The second major project is focused on the vesicular monoamine transporter 2 (VMAT2), an essential transporter for storage and regulation of neurotransmitter signaling, and target for a variety of disorders from diabetes to amphetamine abuse. Despite its biological and medical significance, there is a lack of atomic-level insight into where and how substrates, drugs, or medications bind, or how they modulate VMAT2 function. We will therefore determine crystal structures of VMAT2 bound to various substrates and drugs, elucidate fundamental mechanisms of transport and drug modulation, and characterize the precise architecture of different binding sites. We will further use our molecular insights in structure-based drug discovery, to develop pharmacologically and chemically novel tool compounds for future studies of VMAT2 (patho)biology in in vitro and in vivo. Our studies are both innovative technically and conceptually, as the unique combination of structural, pharmacological, and drug discovery approaches will provide an unprecedented view into the molecular mechanisms of two neglected and understudied 5-HT drug targets.