Structural biology

About: Structural biology is a research topic. Over the lifetime, 2206 publications have been published within this topic receiving 126070 citations.

Interrogating Membrane Protein Conformational Dynamics within Native Lipid Compositions.

Abstract: The interplay between membrane proteins and the lipids of the membrane is important for cellular function, however, tools enabling the interrogation of protein dynamics within native lipid environments are scarce and often invasive. We show that the styrene-maleic acid lipid particle (SMALP) technology can be coupled with hydrogen-deuterium exchange mass spectrometry (HDX-MS) to investigate membrane protein conformational dynamics within native lipid bilayers. We demonstrate changes in accessibility and dynamics of the rhomboid protease GlpG, captured within three different native lipid compositions, and identify protein regions sensitive to changes in the native lipid environment. Our results illuminate the value of this approach for distinguishing the putative role(s) of the native lipid composition in modulating membrane protein conformational dynamics.

Proteins that make sense

Abstract: Publisher Summary This chapter discusses the olfactory receptors and binding proteins that are useful in the understanding of odor sensitivity and discrimination. The odorant-binding proteins are essential for the dynamics of the olfactory system. The expression of a Drosophila odorant receptor in Xenopus oocytes provides direct evidence for its function, and its activation is orders of magnitude slower than normally observed in the in vivo function. Due to the lack of odorant binding proteins (OBPs) in the heterologous system, the response is extremely slow as compared to the dynamics of the insect olfactory system. Also, the kinetic studies demonstrate that the pH dependent conformational change in pheromone-binding protein from Bombyx mori (BmPBP) occurs in less than 4 msec, and structural biology suggests that the conformational change in BmPBP is an intramolecular mechanism for binding and release of pheromones by pheromone-binding proteins. The chapter also shows the possibility that each odor receptor (OR) can be stimulated by a small number of ligands with only one or a few of them reaching the dendrites.

Retrieving functional pathways of biomolecules from single-particle snapshots.

Abstract: A primary reason for the intense interest in structural biology is the fact that knowledge of structure can elucidate macromolecular functions in living organisms. Sustained effort has resulted in an impressive arsenal of tools for determining the static structures. But under physiological conditions, macromolecules undergo continuous conformational changes, a subset of which are functionally important. Techniques for capturing the continuous conformational changes underlying function are essential for further progress. Here, we present chemically-detailed conformational movies of biological function, extracted data-analytically from experimental single-particle cryo-electron microscopy (cryo-EM) snapshots of ryanodine receptor type 1 (RyR1), a calcium-activated calcium channel engaged in the binding of ligands. The functional motions differ substantially from those inferred from static structures in the nature of conformationally active structural domains, the sequence and extent of conformational motions, and the way allosteric signals are transduced within and between domains. Our approach highlights the importance of combining experiment, advanced data analysis, and molecular simulations. There is a great interest in retrieving functional pathways from cryo-EM single-particle data. Here, the authors present an approach that combines cryo-EM with advanced data-analytical methods and molecular dynamics simulations to reveal the functional pathways traversed on experimentally derived energy landscapes using the ryanodine receptor type 1 as an example.

Statistical mechanics of the denatured state of a protein using replica-averaged metadynamics.

Abstract: The characterization of denatured states of proteins is challenging because the lack of permanent structure in these states makes it difficult to apply to them standard methods of structural biology. In this work we use all-atom replica-averaged metadynamics (RAM) simulations with NMR chemical shift restraints to determine an ensemble of structures representing an acid-denatured state of the 86-residue protein ACBP. This approach has enabled us to reach convergence in the free energy landscape calculations, obtaining an ensemble of structures in relatively accurate agreement with independent experimental data used for validation. By observing at atomistic resolution the transient formation of native and non-native structures in this acid-denatured state of ACBP, we rationalize the effects of single-point mutations on the folding rate, stability, and transition-state structures of this protein, thus characterizing the role of the unfolded state in determining the folding process.