UCSF ChimeraX: Tools for structure building and analysis

Protein Science, Journal Year: 2023, Volume and Issue: 32(11)

Published: Sept. 29, 2023

Advances in computational tools for atomic model building are leading to accurate models of large molecular assemblies seen electron microscopy, often at challenging resolutions 3-4 Å. We describe new methods the UCSF ChimeraX modeling package that take advantage machine-learning structure predictions, provide likelihood-based fitting maps, and compute per-residue scores identify errors. Additional model-building assist analysis mutations, post-translational modifications, interactions with ligands. present latest capabilities, including several community-developed extensions. is available free charge noncommercial use https://www.rbvi.ucsf.edu/chimerax.

Language: Английский

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AlphaFold Protein Structure Database in 2024: providing structure coverage for over 214 million protein sequences

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 52(D1), P. D368 - D375

Published: Nov. 2, 2023

The AlphaFold Database Protein Structure (AlphaFold DB, https://alphafold.ebi.ac.uk) has significantly impacted structural biology by amassing over 214 million predicted protein structures, expanding from the initial 300k structures released in 2021. Enabled groundbreaking AlphaFold2 artificial intelligence (AI) system, predictions archived DB have been integrated into primary data resources such as PDB, UniProt, Ensembl, InterPro and MobiDB. Our manuscript details subsequent enhancements archiving, covering successive releases encompassing model organisms, global health proteomes, Swiss-Prot integration, a host of curated datasets. We detail access mechanisms direct file via FTP to advanced queries using Google Cloud Public Datasets programmatic endpoints database. also discuss improvements services added since its release, including Predicted Aligned Error viewer, customisation options for 3D search engine DB.

Language: Английский

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Bringing Structure to Cell Biology with Cryo-Electron Tomography

Annual Review of Biophysics, Journal Year: 2023, Volume and Issue: 52(1), P. 573 - 595

Published: May 9, 2023

Recent advances in cryo-electron microscopy have marked only the beginning of potential this technique. To bring structure into cell biology, modality tomography has fast developed a bona fide situ structural biology technique where structures are determined their native environment, cell. Nearly every step cryo-focused ion beam-assisted electron (cryo-FIB-ET) workflow been improved upon past decade, since first windows were carved cells, unveiling macromolecular networks near-native conditions. By bridging and cryo-FIB-ET is advancing our understanding structure–function relationships environment becoming tool for discovering new biology.

Language: Английский

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Visualizing the disordered nuclear transport machinery in situ

Nature, Journal Year: 2023, Volume and Issue: 617(7959), P. 162 - 169

Published: April 26, 2023

Abstract The approximately 120 MDa mammalian nuclear pore complex (NPC) acts as a gatekeeper for the transport between nucleus and cytosol 1 . central channel of NPC is filled with hundreds intrinsically disordered proteins (IDPs) called FG-nucleoporins (FG-NUPs) 2,3 Although structure scaffold has been resolved in remarkable detail, actual machinery built up by FG-NUPs—about 50 MDa—is depicted an 60-nm hole even highly tomograms and/or structures computed artificial intelligence 4–11 Here we directly probed conformations vital FG-NUP98 inside NPCs live cells permeabilized intact using synthetic biology-enabled site-specific small-molecule labelling approach paired time-resolved fluorescence microscopy. Single cell measurements distance distribution segments combined coarse-grained molecular simulations allowed us to map uncharted environment nanosized channel. We determined that provides—in terminology Flory polymer theory 12 —a ‘good solvent’ environment. This enables FG domain adopt expanded thus control cytoplasm. With more than 30% proteome being formed from IDPs, our study opens window into resolving disorder–function relationships IDPs situ, which are important various processes, such cellular signalling, phase separation, ageing viral entry.

Language: Английский

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Understanding a protein fold: The physics, chemistry, and biology of α-helical coiled coils

Journal of Biological Chemistry, Journal Year: 2023, Volume and Issue: 299(4), P. 104579 - 104579

Published: March 5, 2023

Protein science is being transformed by powerful computational methods for structure prediction and design: AlphaFold2 can predict many natural protein structures from sequence, other AI are enabling the de novo design of new structures. This raises a question: how much do we understand underlying sequence-to-structure/function relationships captured these methods? perspective presents our current understanding one class assembly, α-helical coiled coils. At first sight, straightforward: sequence repeats hydrophobic (h) polar (p) residues, (hpphppp)n, direct folding assembly amphipathic α helices into bundles. However, different bundles possible: they have two or more (different oligomers); parallel, antiparallel, mixed arrangements topologies); helical sequences be same (homomers) (heteromers). Thus, sequence-to-structure must present within hpphppp to distinguish states. I discuss this problem at three levels: first, physics gives parametric framework generate possible coiled-coil backbone Second, chemistry provides means explore deliver relationships. Third, biology shows coils adapted functionalized in nature, inspiring applications synthetic biology. argue that largely understood; partly solved, though considerable challenge predicting even relative stabilities states remains; but there

Language: Английский

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Nuclear transport proteins: structure, function, and disease relevance

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Nov. 10, 2023

Abstract Proper subcellular localization is crucial for the functioning of biomacromolecules, including proteins and RNAs. Nuclear transport a fundamental cellular process that regulates many macromolecules within nuclear or cytoplasmic compartments. In humans, approximately 60 are involved in transport, nucleoporins form membrane-embedded pore complexes, karyopherins cargoes through these Ran system ensure directed rapid transport. Many play additional essential roles mitosis, biomolecular condensation, gene transcription. Dysregulation linked to major human diseases such as cancer, neurodegenerative diseases, viral infections. Selinexor (KPT-330), an inhibitor targeting export factor XPO1 (also known CRM1), was approved 2019 treat two types blood cancers, dozens clinical trials ongoing. This review summarizes three decades research data this field but focuses on structure function individual from recent studies, providing cutting-edge holistic view role health disease. In-depth knowledge rapidly evolving has potential bring new insights into biology, pathogenic mechanisms, therapeutic approaches.

Language: Английский

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AlphaFold2 protein structure prediction: Implications for drug discovery

Current Opinion in Structural Biology, Journal Year: 2023, Volume and Issue: 78, P. 102526 - 102526

Published: Jan. 6, 2023

Language: Английский

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The power and pitfalls of AlphaFold2 for structure prediction beyond rigid globular proteins

Nature Chemical Biology, Journal Year: 2024, Volume and Issue: 20(8), P. 950 - 959

Published: June 21, 2024

Language: Английский

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MoDAFold: a strategy for predicting the structure of missense mutant protein based on AlphaFold2 and molecular dynamics

Briefings in Bioinformatics, Journal Year: 2024, Volume and Issue: 25(2)

Published: Jan. 22, 2024

Abstract Protein structure prediction is a longstanding issue crucial for identifying new drug targets and providing mechanistic understanding of protein functions. To enhance the progress in this field, spectrum computational methodologies has been cultivated. AlphaFold2 exhibited exceptional precision predicting wild-type structures, with performance exceeding that other methods. However, structures missense mutant proteins using remains challenging due to intricate substantial structural alterations caused by minor sequence variations proteins. Molecular dynamics (MD) validated precisely capturing changes amino acid interactions attributed mutations. Therefore, first time, strategy entitled ‘MoDAFold’ was proposed improve accuracy reliability combining MD. Multiple case studies have confirmed superior MoDAFold compared methods, particularly AlphaFold2.

Language: Английский

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Ranking Peptide Binders by Affinity with AlphaFold**

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 62(7)

Published: Dec. 21, 2022

AlphaFold has revolutionized structural biology by predicting highly accurate structures of proteins and their complexes with peptides other proteins. However, for protein-peptide systems, we are also interested in identifying the highest affinity binder among a set candidate peptides. We present novel competitive binding assay using to predict receptor presence two For systems which individual well predicted, captures higher bound state, peptide unbound form statistical significance. test application on six protein receptors have experimental affinities several find that is best suited medium strong binders adopt stable secondary upon binding.

Language: Английский

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