Method development for the identification and characterization of low-affinity ligand-binding sites on protein targets using X-ray crystallography

使用 X 射线晶体学鉴定和表征蛋白质靶标上低亲和力配体结合位点的方法开发

• 批准号: 521308-2017
• 负责人: Calmettes, Charles
• 金额: $ 1.82万
• 依托单位: Institut national de la recherche scientifique
• 依托单位国家: 加拿大
• 项目类别: Engage Grants Program
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=639701
• 关键词: Method; development; identification; characterization; low

The grant proposal consists in establishing a method to locate and characterize the binding pockets of smallmolecule ligands (so called fragments) onto a protein target, at atomic resolution. NMX Research andSolutions Inc. is a research organization specialized in drug discovery and fragment screening using nuclearmagnetic resonance spectroscopy. The company aims at developing novel methods for the screening offragment and small molecule onto proteins. Such challenging project requires highly sensitive biophysicalmethods to obtain high-resolution structural information. Hence, understanding how low-affinity fragmentsbind to proteins remains a fundamental question and a technical challenge raised by NMX Research andSolutions. Dr. Calmettes, expert in protein structures and X-ray crystallography, will develop for NMXResearch and Solutions an alternative method to identify and locate low-affinity fragment-binding sites onproteins using protein X-ray crystallography. Only a few groups in Canada have the expertise in preparing,crystallizing, and solving protein structures. This project is highly relevant for the Canadian industry and theadvancement of knowledge in Canada; it is anticipated to open new avenues for the design of protein regulatorfor a variety of applications in biotechnology, bioscience and bio-industrial sectors in Canada.

该拨款提案包括建立一种方法，以原子分辨率定位和表征小分子配体（所谓的片段）与蛋白质目标的结合口袋。NMX Research and solutions Inc.是一家专门从事核磁共振光谱药物发现和片段筛选的研究机构。该公司致力于开发新的方法来筛选片段和小分子到蛋白质上。这样具有挑战性的项目需要高度敏感的生物物理方法来获得高分辨率的结构信息。因此，了解低亲和力片段如何与蛋白质结合仍然是NMX研究和解决方案提出的一个基本问题和技术挑战。Calmettes博士是蛋白质结构和x射线晶体学方面的专家，他将为NMXResearch and Solutions开发一种替代方法，利用蛋白质x射线晶体学来识别和定位蛋白质上的低亲和力片段结合位点。在加拿大，只有少数几个小组具有制备、结晶和解决蛋白质结构的专业知识。该项目与加拿大工业和加拿大知识的进步高度相关；预计将为加拿大生物技术、生物科学和生物工业部门各种应用的蛋白质调节剂的设计开辟新的途径。