Simulation and Machine Learning Methods for Ion-Channel Structure Determination, Mechanistic Studies and Drug Design DOI Creative Commons
Zhengdan Zhu,

Zhenfeng Deng,

Qinrui Wang

et al.

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: June 28, 2022

Ion channels are expressed in almost all living cells, controlling the in-and-out communications, making them ideal drug targets, especially for central nervous system diseases. However, owing to their dynamic nature and presence of a membrane environment, ion remain difficult targets past decades. Recent advancement cryo-electron microscopy computational methods has shed light on this issue. An explosion high-resolution channel structures paved way structure-based rational design state-of-the-art simulation machine learning techniques dramatically improved efficiency effectiveness computer-aided design. Here we present an overview how learning-based fundamentally changed channel-related at different levels, as well emerging trends field.

Language: Английский

AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models DOI Creative Commons
Mihály Váradi, Stephen Anyango, Mandar Deshpande

et al.

Nucleic Acids Research, Journal Year: 2021, Volume and Issue: 50(D1), P. D439 - D444

Published: Oct. 19, 2021

The AlphaFold Protein Structure Database (AlphaFold DB, https://alphafold.ebi.ac.uk) is an openly accessible, extensive database of high-accuracy protein-structure predictions. Powered by v2.0 DeepMind, it has enabled unprecedented expansion the structural coverage known protein-sequence space. DB provides programmatic access to and interactive visualization predicted atomic coordinates, per-residue pairwise model-confidence estimates aligned errors. initial release contains over 360,000 structures across 21 model-organism proteomes, which will soon be expanded cover most (over 100 million) representative sequences from UniRef90 data set.

Language: Английский

Citations

6187
Drug discovery is an eternal challenge for the biomedical sciences DOI Creative Commons
Hua Li, Wenyi Wei, Hong‐Xi Xu

et al.

Acta Materia Medica, Journal Year: 2022, Volume and Issue: 1(1)

Published: Jan. 1, 2022

In this inaugural Editorial the Co-Editors-in-Chief and Executive Editor of Acta Materia Medica Hua Li Wenyi Wei Hongxi Xu discuss how drug discovery is an eternal challenge for biomedical sciences. The new drugs among humanity’s most sophisticated cutting-edge intellectual activities. This process requires not only […]

Language: Английский

Citations

104
RCSB Protein Data Bank: Efficient Searching and Simultaneous Access to One Million Computed Structure Models Alongside the PDB Structures Enabled by Architectural Advances DOI Creative Commons
Sebastian Bittrich, Charmi Bhikadiya,

Chunxiao Bi

et al.

Journal of Molecular Biology, Journal Year: 2023, Volume and Issue: 435(14), P. 167994 - 167994

Published: Feb. 2, 2023

The Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB) provides open access to experimentally-determined three-dimensional (3D) structures of biomolecules. RCSB PDB RCSB.org research-focused web portal is used annually by many millions users around the world. They biostructure information, run complex queries utilizing various search services (e.g., full-text, structural and chemical attribute, chemical, sequence, structure similarity searches), visualize macromolecules in 3D, all at no charge with limitations on data usage. Notwithstanding more than 24,000-fold growth over past five decades, are only available a small subset proteins known sequence. Recently developed machine learning software tools can predict 3D accuracies comparable lower-resolution experimental methods. now ∼1,000,000 Computed Structure Models (CSMs) coming from AlphaFold DB ModelArchive alongside ∼200,000 structures. Both CSMs via well-established Data, Search, 1D-Coordinates application programming interfaces (APIs). Simultaneous delivery complementary information across human proteome those model organisms selected pathogens. API enhancements backwards-compatible programmatic "opt in" minimal effort. Herein, we describe modifications cyberinfrastructure required support sixfold scaling lay groundwork accommodate hundreds CSMs.

Language: Английский

Citations

43
PARP Power: A Structural Perspective on PARP1, PARP2, and PARP3 in DNA Damage Repair and Nucleosome Remodelling DOI Open Access
Lotte van Beek, Éilís McClay,

Saleha Patel

et al.

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(10), P. 5112 - 5112

Published: May 12, 2021

Poly (ADP-ribose) polymerases (PARP) 1-3 are well-known multi-domain enzymes, catalysing the covalent modification of proteins, DNA, and themselves. They attach mono- or poly-ADP-ribose to targets using NAD+ as a substrate. Poly-ADP-ribosylation (PARylation) is central important functions PARP enzymes in DNA damage response nucleosome remodelling. Activation happens through binding via zinc fingers and/or WGR domain. Modulation their activity inhibitors occupying site has proven successful cancer therapies. For decades, studies set out elucidate full-length molecular structure activation mechanism. In last five years, significant advances have progressed structural functional understanding PARP1-3, such allosteric inter-domain contacts, how senses damaged crowded nucleus, complementary role histone PARylation factor 1 modulating active PARP. Here, we review these together with versatility domains involved binding, shape PARPs

Language: Английский

Citations

68
Molecular interactions at the colchicine binding site in tubulin: An X-ray crystallography perspective DOI Creative Commons
Jiaxing Wang, Duane D. Miller, Wěi Li

et al.

Drug Discovery Today, Journal Year: 2021, Volume and Issue: 27(3), P. 759 - 776

Published: Dec. 8, 2021

Language: Английский

Citations

62
Structural basis of efficacy-driven ligand selectivity at GPCRs DOI Creative Commons

Alexander S. Powers,

Vi Pham, Wessel A. C. Burger

et al.

Nature Chemical Biology, Journal Year: 2023, Volume and Issue: 19(7), P. 805 - 814

Published: Feb. 13, 2023

A drug's selectivity for target receptors is essential to its therapeutic utility, but achieving between similar challenging. The serendipitous discovery of ligands that stimulate more strongly than closely related receptors, despite binding with affinities, suggests a solution. molecular mechanism such 'efficacy-driven selectivity' has remained unclear, however, hindering design ligands. Here, using atomic-level simulations, we reveal the structural basis efficacy-driven long-studied clinical drug candidate, xanomeline, muscarinic acetylcholine (mAChRs). Xanomeline's mode across mAChRs in their inactive states differs active states, divergent effects on active-state stability. We validate this experimentally and use it altered selectivity. Our results suggest strategies rational achieve many pharmaceutically important G-protein-coupled receptors.

Language: Английский

Citations

37
Targeting SLC transporters: small molecules as modulators and therapeutic opportunities DOI Creative Commons
Avner Schlessinger, Nicole Zatorski, Keino Hutchinson

et al.

Trends in Biochemical Sciences, Journal Year: 2023, Volume and Issue: 48(9), P. 801 - 814

Published: June 22, 2023

Language: Английский

Citations

35
Deep Learning-Based Segmentation of Cryo-Electron Tomograms DOI Open Access

Jessica Heebner,

Carson Purnell, Ryan Hylton

et al.

Journal of Visualized Experiments, Journal Year: 2022, Volume and Issue: 189

Published: Nov. 11, 2022

Cryo-electron tomography (cryo-ET) allows researchers to image cells in their native, hydrated state at the highest resolution currently possible. The technique has several limitations, however, that make analyzing data it generates time-intensive and difficult. Hand segmenting a single tomogram can take from hours days, but microscope easily generate 50 or more tomograms day. Current deep learning segmentation programs for cryo-ET do exist, are limited one structure time. Here, multi-slice U-Net convolutional neural networks trained applied automatically segment multiple structures simultaneously within cryo-tomograms. With proper preprocessing, these be robustly inferred many without need training individual each tomogram. This workflow dramatically improves speed with which cryo-electron analyzed by cutting time down under 30 min most cases. Further, segmentations used improve accuracy of filament tracing cellular context rapidly extract coordinates subtomogram averaging.

Language: Английский

Citations

29
Structural analysis of cancer-relevant TCR-CD3 and peptide-MHC complexes by cryoEM DOI Creative Commons
Kei Saotome, Drew Dudgeon,

Kiersten Colotti

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: April 26, 2023

The recognition of antigenic peptide-MHC (pMHC) molecules by T-cell receptors (TCR) initiates the mediated immune response. Structural characterization is key for understanding specificity TCR-pMHC interactions and informing development therapeutics. Despite rapid rise single particle cryoelectron microscopy (cryoEM), x-ray crystallography has remained preferred method structure determination complexes. Here, we report cryoEM structures two distinct full-length α/β TCR-CD3 complexes bound to their pMHC ligand, cancer-testis antigen HLA-A2/MAGEA4 (230-239). We also determined pMHCs containing MAGEA4 (230-239) peptide closely related MAGEA8 (232-241) in absence TCR, which provided a structural explanation preference displayed TCRs. These findings provide insights into TCR clinically relevant cancer demonstrate utility high-resolution analysis interactions.

Language: Английский

Citations

21
Blockade of KLF5/LDH—A feedback loop contributes to Curcumol inhibition of sinusoidal endothelial cell glycolysis and mitigation of liver fibrosis DOI
Yang Li, Yuanyuan Zhou,

Siwei Xia

et al.

Phytomedicine, Journal Year: 2023, Volume and Issue: 114, P. 154759 - 154759

Published: March 22, 2023

Language: Английский

Citations

16