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Structural biology

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


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Journal ArticleDOI
04 Dec 2008-Nature
TL;DR: The route by which TLR9 and TLR7 exit the endoplasmic reticulum and travel to endolysosomes in mouse macrophages and dendritic cells is defined and it is proposed that ectodomain cleavage represents a strategy to restrict receptor activation to endophilic compartments and prevent TLRs from responding to self nucleic acids.
Abstract: Mammalian Toll-like receptors (TLRs) 3, 7, 8 and 9 initiate immune responses to infection by recognizing microbial nucleic acids; however, these responses come at the cost of potential autoimmunity owing to inappropriate recognition of self nucleic acids. The localization of TLR9 and TLR7 to intracellular compartments seems to have a role in facilitating responses to viral nucleic acids while maintaining tolerance to self nucleic acids, yet the cell biology regulating the transport and localization of these receptors remains poorly understood. Here we define the route by which TLR9 and TLR7 exit the endoplasmic reticulum and travel to endolysosomes in mouse macrophages and dendritic cells. The ectodomains of TLR9 and TLR7 are cleaved in the endolysosome, such that no full-length protein is detectable in the compartment where ligand is recognized. Notably, although both the full-length and cleaved forms of TLR9 are capable of binding ligand, only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. Furthermore, conditions that prevent receptor proteolysis, including forced TLR9 surface localization, render the receptor non-functional. We propose that ectodomain cleavage represents a strategy to restrict receptor activation to endolysosomal compartments and prevent TLRs from responding to self nucleic acids.

562 citations

Journal ArticleDOI
TL;DR: The membrane-bound Toll-like receptors trigger innate immune responses after recognition of a wide variety of pathogen-derived compounds and the nature of the interactions of the TLR extracellular domains with their ligands varies markedly between TLR paralogs.

547 citations

Journal ArticleDOI
TL;DR: Main approaches to the characterization of proteins and protein complexes using SAXS are reviewed, and main tools for the analysis of proteins in solution are presented, and the impact that these tools have made in modern structural biology is discussed.

517 citations

Journal ArticleDOI
01 Dec 2015-eLife
TL;DR: An image classification procedure is described that characterizes molecular plasticity at the secondary structure level, and applies this method to identify three distinct conformations in a previous sample of γ-secretase, revealing how conformational mobility in the second and sixth transmembrane helices of presenilin is greatly reduced upon binding of DAPT or the additional helix, and form the basis for a new model of how substrate enters the trans Membrane domain.
Abstract: An enzyme called gamma-secretase cuts other proteins in cells into smaller pieces. Like most enzymes, gamma-secretase is expected to move through several different three-dimensional shapes to perform its role, and identifying these structures could help us to understand how the enzyme works. One of the proteins that is targeted by gamma-secretase is called amyloid precursor protein, and cutting this protein results in the formation of so-called amyloid-beta peptides. When gamma-secretase doesn't work properly, these amyloid-beta peptides can accumulate in the brain and large accumulations of these peptides have been observed in the brains of patients with Alzheimer's disease. Earlier in 2015, a group of researchers used a technique called cryo-electron microscopy (cryo-EM) to produce a three-dimensional model of gamma-secretase. This revealed that the active site of the enzyme, that is, the region that is used to cut the other proteins, is particularly flexible. Now, Bai et al. – including many of the researchers from the earlier work – studied this flexibility in more detail. For the experiments, gamma-secretase was exposed to an inhibitor molecule that stopped it from cutting other proteins. This meant that the structure of gamma-secretase became more rigid than normal, which made it possible to collect more detailed structural information using cryo-EM. Bai et al. also developed new methods for processing images to separate the images of individual enzyme molecules based on the different shapes they had adopted at the time. These methods make it possible to view a mixture of very similar enzyme structures that differ only in a small region of the protein (in this case the active site). In the future, it would be useful to repeat these imaging experiments using a range of different molecules that alter the activity of gamma-secretase. Furthermore, the new image processing methods developed by Bai et al. could be used to study flexibility in the shapes of other proteins.

515 citations

Journal ArticleDOI
TL;DR: Insights from computational studies of affinities of ligands binding to proteins are reviewed to elucidate how motions and ensembles and alternative conformers and the entropies and forces that cannot be seen in single molecular structures also contribute to binding affinITIES.

510 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
202335
202272
2021149
2020154
2019152
2018140