James S. Fraser

Learning inhibitor interactions from protein deep mutational scanning data and deep learning models

The paper benchmarks AI models for predicting mutational effects and drug-target affinity using deep mutational scanning data, finding that current models fail to capture inhibitor-dependent fitness landscapes.

Distinct activation mechanisms underlie ligand efficacy at a GPCR

This study uses deep mutational pharmacology to show how different residues in the -opioid receptor determine the efficacy of opioids by shaping distinct activation mechanisms.

Large scale prospective evaluation of co-folding across hundreds of Mac1-ligand complexes and three virtual screens

On 489 evaluable new Mac1 complexes, AlphaFold3, Chai-1 and Boltz-2 placed over half of ligands within 2 Å, but on docking hit-lists AF3 and Boltz-2 added little over docking.

Product-stabilized filamentation by human glutamine synthetase allosterically tunes metabolic activity

This paper shows human glutamine synthetase forms filaments stabilized by glutamine, reducing catalytic specificity for ammonia and linking product concentration to enzyme function.

Structural Plasticity and Ligand Promiscuity of CYP3A4 Revealed by Cryo-EM

This study uses cryo-EM to reveal structural plasticity and ligand promiscuity of CYP3A4, showing multiple conformations and highlighting the F/G loop's role in binding pocket remodeling.

Inhibiting the interaction between the mitochondrial receptor Tom70 and SARS CoV 2 Orf9b with small molecules

This paper identifies two strategies to modulate the Orf9b-Tom70 interaction by screening for small molecules that either stabilize Orf9b dimer or block its binding to Tom70, with potential to restore interferon signaling against SARS-CoV-2.

A Unified 3D Generative Model for Synthesizable Structure-Based Drug Design

This paper introduces LDDM, a generative model for drug design that produces synthetically accessible compounds validated experimentally for five protein targets.

Structure-based discovery of inhibitors of Mac1 domain of nonstructural protein-3 of SARS-CoV-2 by machine learning-augmented screening of chemical space

The paper uses machine learning-augmented virtual screening to discover a novel series of Mac1 inhibitors for SARS-CoV-2 NSP3, validated by experimental assays and crystallography.

Programming protein shape as an explicit design layer via CAD blueprint-guided diffusion

The paper integrates CAD blueprints with diffusion models to explicitly program protein shapes, demonstrating emergent functions through molecular design.

Structural adaptations for enhanced translation kinetics in evolved ribosomes

This study structurally characterizes evolved ribosomes with enhanced translation kinetics, revealing how RNA structural adaptations influence translation efficiency.

Evaluating beta-tubulin variants as predictors of benzimidazole resistance across Caenorhabditis nematodes

The paper identifies beta-tubulin variants associated with benzimidazole resistance in three Caenorhabditis species and shows species-specific patterns of resistance.

Coronavirus protein interaction mapping in bat and human cells identifies molecular and genetic switches for immune evasion and replication

Toward a Random Background for Ligand Optimization

This study systematically evaluates the effectiveness of random small perturbations in ligand optimization, finding 11.2% of analogs improved potency by ≥10-fold but often had worse pharmacokinetics.

Emergence of specific binding and catalysis from a designed generalist binding protein

This study shows how a designed generalist binding protein can evolve into specific functions like a fluorophore binder and an efficient enzyme through weak, promiscuous interactions.

Structural modification of oxazolidinone antibiotics alters nascent peptide stalling preference and peptide trajectory through the ribosome

This study shows that structural modifications of oxazolidinone antibiotics alter their preference for specific penultimate amino acids during translation inhibition.

Discovery of AVI-6451, a Potent and Selective Inhibitor of the SARS-CoV-2 ADP-Ribosylhydrolase Mac1 with Oral Efficacy in vivo

This paper identifies AVI-6451, an orally bioavailable inhibitor of SARS-CoV-2 Mac1 with once-daily efficacy in a mouse model.

Autoregulation of the MET Receptor Tyrosine Kinase by its Intracellular Juxtamembrane Domain

This study identifies a role for the MET juxtamembrane domain in accelerating kinase activation through an allosteric mechanism, with implications for MET-driven cancer therapies.

Crystallographic Ensembles Reveal the Structural Basis of Binding Entropy in SARS-CoV2 Macrodomain

The paper uses crystallographic ensembles to quantify conformational entropy changes in SARS-CoV-2 Macrodomain upon ligand binding, linking structural heterogeneity to binding thermodynamics.

The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2

This study identifies Mac1 as a therapeutic target for SARS-CoV-2 and demonstrates that AVI-4206, a small molecule inhibitor, reduces viral replication and improves survival in an animal model.

Macrodomain catalytic activity modulates Chikungunya virus dissemination and transmission potential in Aedes mosquitoes

This study shows that CHIKV macrodomain catalytic activity affects virus replication and transmission in Aedes mosquitoes, with mutation-specific outcomes in different host contexts.

Bayesian multi-state multi-condition modeling of a protein structure based on X-ray crystallography data

The paper develops MultiXray, a Bayesian method for multi-state and multi-condition protein structure modeling using X-ray crystallography data, improving Rfree values in both simulated and experimental cases.

Distal mutations enhance catalysis in designed enzymes by facilitating substrate binding and product release

This study shows that distal mutations improve enzyme catalysis by enhancing substrate binding and product release, working with active-site mutations to increase overall activity.

Rosace-AA: Enhancing Interpretation of Deep Mutational Scanning Data with Amino Acid Substitution and Position-Specific Insights

Initial leads to combat streptogramin resistance generated from X-ray fragment screening against VatD

This study identifies fragment-based inhibitors of VatD, an enzyme responsible for streptogramin resistance, using X-ray crystallography to guide inhibitor development.

Coupled equilibria of dimerization and lipid binding modulate SARS Cov 2 Orf9b interactions and interferon response

This study develops a biophysical model to show how lipid binding and mutations affect Orf9b's conformational equilibrium and its interaction with Tom70, influencing interferon suppression.

AcrIF11 is a potent CRISPR-specific ADP-ribosyltransferase encoded by phage and plasmid

This study characterizes AcrIF11, an ADP-ribosyltransferase that inhibits CRISPR-Cas systems with high potency and specificity, and shows its reversibility through macrodomain enzymes.

Expanding Automated Multiconformer Ligand Modeling to Macrocycles and Fragments

The paper improves qFit-ligand to better model ligand conformations in structural data, enhancing analysis of conformational heterogeneity in ligand-bound structures.

Extensive exploration of structure activity relationships for the SARS-CoV-2 macrodomain from shape-based fragment merging and active learning

Shape-based fragment merging (FrankenROCS) with Thompson sampling over 22 billion molecules found neutral SARS-CoV-2 macrodomain inhibitors; analogs reached single-digit micromolar IC50, backed by 137 crystal structures.

Mapping kinase domain resistance mechanisms for the MET receptor tyrosine kinase via deep mutational scanning

The paper uses deep mutational scanning to analyze MET kinase domain mutations and their resistance to 11 inhibitors, identifying resistance and sensitizing mutations and improving prediction with a protein language model.

Context-specific inhibition of mitochondrial ribosomes by phenicol and oxazolidinone antibiotics

This study investigates how chloramphenicol and oxazolidinone antibiotics inhibit mitochondrial ribosomes, finding context-specific stalling similar to their bacterial action.