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Atomic Level Analysis of Biomolecular Structure

生物分子结构的原子水平分析

基本信息

批准号：
10246938
负责人：
WAYNE A. HENDRICKSON
金额：
$ 39.69万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-03 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10246938
关键词：
Biological Calcium Classification Cryoelectron Microscopy Crystallization Data Data Collection Data Set Development Devices Diffusion Electron Microscopy Evaluation Evolution Formulation Health Heart failure Human Infection Ligands Light Lipids Malignant Neoplasms Maps Masks Membrane Proteins Methods Modeling Molecular Chaperones Molecular Conformation Neurodegenerative Disorders Noise Pattern Phase Philosophy Phosphorus Preparation Probability Procedures Property Proteins Radiation induced damage Resolution Roentgen Rays Science Signal Transduction Structure Sulfur System Time Ursidae Family Validation X ray diffraction analysis X-Ray Crystallography absorption base computerized data processing computerized tools cryogenics density design experience experimental study flexibility improved instrumentation interest macromolecule method development microbial novel protein-histidine kinase radiation effect radiation mitigation receptor structural biology technology development virtual

项目摘要

Atomic Level Analysis of Biomolecular Structure The overall objective of this proposal is to develop enhanced methods for analyzing structures of biological macromolecules at an atomic level of resolution. We build on our recent accomplishments and worldwide experience showing that single- and multi-wavelength anomalous diffraction (SAD and MAD) now predominate for de novo determinations of macromolecular crystal structures. We also build on the evolution of our own efforts in high-resolution structure determination to include analyses by cryogenic electron microscopy (cryo-EM). Our philosophy is to drive the development of methods by the demands of compelling applications to current problems of biological significance. We propose to optimize SAD and MAD phasing procedures and to enhance cryo-EM analyses of biomolecules at the atomic level in the course of studies of membrane proteins, macromolecular assemblages, eukaryotic proteins and other challenges. The overall objective is embodied in three specific aims: (1) We propose to enhance anomalous diffraction phasing procedures for challenging problems. One focus is on improved methods for increasing signal-to-noise ratios for anomalous diffraction by combining data from many crystals. A second focus is on enhanced MAD procedures for accurate experimental phase evaluation. (2) We propose to develop methods for the manipulation and diffraction analysis of microcrystals. One focus is on intrinsically small crystals, such as those of membrane proteins grown in lipidic cubic phase; and a second focus is on microcrystals purposed for the minimization of absorption, as is needed for low-energy native SAD experiments, or for rapid diffusion in time-resolved experiments. (3) We propose to enhance methods for analyzing cryo-EM structures using experience gained in analyzing x-ray crystal structures and in validating the fittings of atomic model interpretations to experimental EM maps.

生物分子结构的原子能级分析这项建议的总体目标是开发改进的方法来分析结构原子分辨率的生物大分子。我们在最近取得的成就的基础上再接再厉世界范围内的经验表明，单波长和多波长反常衍射(SAD和 MAD)现在主要用于大分子晶体结构的从头测定。我们还建立了关于我们自己在高分辨率结构确定方面的努力的演变，以包括由低温电子显微镜(低温电子显微镜)。我们的理念是通过以下方式推动方法的发展对当前具有生物学意义的问题的强制性应用的要求。我们建议优化SAD和MAD阶段程序并加强对生物分子的冷冻-EM分析膜蛋白、大分子组合、真核生物研究过程中的原子水平蛋白质和其他挑战。总体目标体现在三个具体目标上：(一)我们建议加强异常衍射位相程序，以解决具有挑战性的问题。其中一个焦点是结合数据提高异常绕射信噪比的改进方法从许多水晶中提取。第二个重点是针对准确的实验阶段的增强的mad程序。评估。(2)我们提出了处理和衍射分析的方法。微晶。一个焦点是本质上很小的晶体，比如生长在脂类立方相；第二个焦点是用于最小化吸收的微晶体，如低能量原生SAD实验所需，或时间分辨的快速扩散实验。(3)提出了改进经验分析低温电磁结构的方法在分析x射线晶体结构和验证原子模型解释的拟合中获得到实验性的电磁地图。

项目成果

期刊论文数量（27）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Facing the phase problem.

DOI：
10.1107/s2052252523006449
发表时间：
2023-09-01
期刊：
IUCrJ
影响因子：
3.9
作者：
通讯作者：

Multi-crystal native-SAD phasing at 5 keV with a helium environment.

DOI：
10.1107/s205225252200971x
发表时间：
2022-11-01
期刊：
IUCrJ
影响因子：
3.9
作者：
通讯作者：

Contemporary Use of Anomalous Diffraction in Biomolecular Structure Analysis.

DOI：
10.1007/978-1-4939-7000-1_16
发表时间：
2017
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Liu Q;Hendrickson WA
通讯作者：
Hendrickson WA

Fine Sampling of Sequence Space for Membrane Protein Structural Biology.

DOI：
10.1016/j.jmb.2021.167055
发表时间：
2021-07-23
期刊：
Journal of molecular biology
影响因子：
5.6
作者：
Loukeris M;Sanghai ZA;Vendome J;Hendrickson WA;Kloss B;Mancia F
通讯作者：
Mancia F

Crystal structure of LGR ligand α2/β5 from Caenorhabditis elegans with implications for the evolution of glycoprotein hormones.

DOI：
10.1073/pnas.2218630120
发表时间：
2023-01-03
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Gong, Zhen;Wang, Wei;El Omari, Kamel;Lebedev, Andrey A.;Clarke, Oliver B.;Hendrickson, Wayne A.
通讯作者：
Hendrickson, Wayne A.