Plasticity in the Recognition of Flexible Ligands

本研究旨在了解结构可塑性在介导蛋白质结构域与柔性配体之间的结合特异性和亲和力中的作用。 配体的特异性识别是许多蛋白质的关键功能，并且形成协调中心生物过程活动的广泛网络的基础。 在许多生物学背景下，蛋白质结构域在功能上识别相关配体家族，同时区分结构相似的配体。 待检验的假设是，相关配体的识别在结构上比从蛋白质-配体复合物的单一结构中推断出的更多样化。 作为本研究计划的一部分，对生物分子界面处采用的构象集合进行严格的生化和结构分析，将有助于我们了解配体结合特异性的潜在机制。 此外，这些知识将为旨在理解和预测配体结合特异性的计算工作提供见解。 这项工作将大大推进我们对蛋白质-配体相互作用特异性机制的理解，这对各种生物功能至关重要。 此外，结构和生物化学数据将补充其他人正在进行的旨在模拟蛋白质-配体相互作用的计算研究。 此外，这里概述的计划促进教学，培训和学习，同时推进科学发现。 这些活动通过精心设计和周到的博士后研究员和研究生指导计划，以及通过在本科课堂教学创新发生。 PI还参加了几个方案，以增加代表性不足的群体，包括妇女和少数民族在科学中的参与，从教师，博士后研究员和研究生职业指导到定制研究生课程，以促进代表性不足的少数民族的招聘和保留。 该计划支持使用我们的区域高场NMR设施，包括配备低温探头的800和900 MHz仪器。 除了传播研究成果的正常途径，包括同行评审的出版物和在科学会议上的演讲，PI通过当地学校的科学活动参与社区外展，并作为CU向导，策划社区科学展。

This research project aims to understand the role of structural plasticity in mediating binding specificity and affinity between protein domains and flexible ligands. The specific recognition of a ligand is the key function of many proteins, and forms the basis of the extensive networks that coordinate the activities of central biological processes. In many biological contexts, a protein domain functionally recognizes a family of related ligands while discriminating against structurally similar ligands. The hypothesis to be tested is that the recognition of related ligands is more structurally diverse than can be inferred from a single structure of a protein-ligand complex. The rigorous biochemical and structural analysis of the ensemble of conformations adopted at biomolecular interfaces that is part of this research program will contribute to our understanding of the underlying mechanisms of ligand-binding specificity. Furthermore, this knowledge will provide insights for computational efforts aimed at understanding and predicting ligand-binding specificity. This work will significantly advance our understanding of the mechanisms that confer specificity in protein-ligand interactions, which are essential to a wide variety of biological functions. In addition, the structural and biochemical data will complement ongoing computational studies by others that seek to model protein-ligand interactions. Furthermore, the program outlined here promotes teaching, training and learning while advancing scientific discovery. These activities occur through a well-designed and thoughtful postdoctoral fellow and graduate student mentoring program, as well as through teaching innovations in the undergraduate classroom. The PI also participates in several programs to increase the participation of under-represented groups, including women and minorities in science, ranging from faculty, postdoctoral fellow and graduate student career mentoring to tailoring the graduate curriculum to facilitate recruitment and retention of under-represented minorities. This program supports the use of our regional high field NMR facilities, including 800 and 900 MHz instruments equipped with cryogenic probes. In addition to the normal avenues of dissemination of research findings, including peer-reviewed publication and presentations at scientific meetings, the PI participates in community outreach through science activities at local schools and as a CU Wizard, orchestrating a community science show.