Journey to the center of the protein: allostery from multitemperature multiconformer X-ray crystallography
| Autor: | Daniel A. Keedy |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular Protein Conformation Allosteric regulation conformational heterogeneity Crystallography X-Ray Ligands 03 medical and health sciences 0302 clinical medicine Allosteric Regulation Structural Biology Catalytic Domain Pressure Animals Humans Cryogenic temperature 030304 developmental biology Physics 0303 health sciences Protein function allostery protein flexibility fungi Temperature food and beverages Proteins A protein Hydrogen-Ion Concentration Research Papers X-ray crystallography multitemperature crystallography Thermodynamics Biological system Allosteric Site 030217 neurology & neurosurgery multiconformer modeling MMX |
| Zdroj: | Acta Crystallographica. Section D, Structural Biology |
| ISSN: | 2059-7983 |
| DOI: | 10.1107/s2059798318017941 |
| Popis: | Crystallography at multiple temperatures can reveal the collective shifts of alternative conformations that underlie allosteric communication through protein structures. Proteins inherently fluctuate between conformations to perform functions in the cell. For example, they sample product-binding, transition-state-stabilizing and product-release states during catalysis, and they integrate signals from remote regions of the structure for allosteric regulation. However, there is a lack of understanding of how these dynamic processes occur at the basic atomic level. This gap can be at least partially addressed by combining variable-temperature (instead of traditional cryogenic temperature) X-ray crystallography with algorithms for modeling alternative conformations based on electron-density maps, in an approach called multitemperature multiconformer X-ray crystallography (MMX). Here, the use of MMX to reveal alternative conformations at different sites in a protein structure and to estimate the degree of energetic coupling between them is discussed. These insights can suggest testable hypotheses about allosteric mechanisms. Temperature is an easily manipulated experimental parameter, so the MMX approach is widely applicable to any protein that yields well diffracting crystals. Moreover, the general principles of MMX are extensible to other perturbations such as pH, pressure, ligand concentration etc. Future work will explore strategies for leveraging X-ray data across such perturbation series to more quantitatively measure how different parts of a protein structure are coupled to each other, and the consequences thereof for allostery and other aspects of protein function. |
| Databáze: | OpenAIRE |
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