Violetta Weinreb

Structure-guided design of partial agonists at an opioid receptor

Kevin Appourchaux, Jay P. McLaughlin, Jhoan Aguilar, Haylee R. Hammond et autres

Chronic pain and opioid overdose deaths highlight the need for non-addictive analgesics with novel mechanisms. The δ opioid receptor (δOR) is a promising target, as it lacks the respiratory depression associated with µ opioid receptor (µOR) agonists. However, early δOR full agonists …

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Structure-guided design of partial agonists at an opioid receptor

Balázs R. Varga, Sarah M. Bernhard, Amal El Daibani, Saheem A. Zaidi et autres

Chronic pain and opioid overdose deaths highlight the need for non-addictive analgesics with novel mechanisms. The δ opioid receptor (δOR) is a promising target, as it lacks the respiratory depression associated with µ opioid receptor (µOR) agonists. However, early δOR full agonists …

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High-throughput thermal denaturation of tryptophanyl-tRNA synthetase combinatorial mutants reveals high-order energetic coupling determinants of conformational stability

Violetta Weinreb, Gabriel E. Weinreb, Charles W. Carter

Landscape descriptions provide a framework for identifying functionally significant dynamic linkages in proteins but cannot supply details. Rate measurements of combinatorial mutations can implicate dynamic linkages in catalysis. A major difficulty is filtering dynamic linkages from the vastly more numerous static interactions …

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Changes in cell surface excess are coordinated with protrusion dynamics during 3D motility

Maryna Kapustina, Donna Li, James Zhu, Brittany Wall et autres

To facilitate rapid changes in morphology without endangering cell integrity, each cell possesses a substantial amount of cell surface excess (CSE) that can be promptly deployed to cover cell extensions. CSE can be stored in different types of small surface projections such …

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Cell surface excess is essential for protrusions and motility in 3D matrix

Maryna Kapustina, Donna Li, James Zhu, Brittany Wall et autres

ABSTRACT To facilitate rapid changes in morphology without endangering cell integrity, each cell possesses a substantial amount of cell surface excess (CSE) that can be promptly deployed to cover cell extensions. CSE can be stored in different types of small surface projections …

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A Minimal TrpRS Catalytic Domain Supports Sense/Antisense Ancestry of Class I and II Aminoacyl-tRNA Synthetases

Violetta Weinreb, Glenn L. Butterfoss, Charles W. Carter, Yen Pham et autres

The emergence of polypeptide catalysts for amino acid activation, the slowest step in protein synthesis, poses a significant puzzle associated with the origin of biology. This problem is compounded as the 20 contemporary aminoacyl-tRNA synthetases belong to two quite distinct families. We …

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A Conformational Transition State Accompanies Tryptophan Activation by B. stearothermophilus Tryptophanyl-tRNA Synthetase

Violetta Weinreb, Li Li, Brian Kuhlman, Charles W. Carter et autres

B. stearothermophilus tryptophanyl-tRNA synthetase catalysis proceeds via high-energy protein conformations. Unliganded MD trajectories of the Pre-Transition-state complex with Mg2+•ATP and the (post) transition-state analog complex with adenosine tetraphosphate relax rapidly in opposite directions, the former regressing, the latter progressing along the structural …

Histidyl-tRNA Synthetase Urzymes: CLASS I AND II AMINOACYL tRNA SYNTHETASE URZYMES HAVE COMPARABLE CATALYTIC ACTIVITIES FOR COGNATE AMINO ACID ACTIVATION

Charles W. Carter, Li Li, Violetta Weinreb, Christopher S. Francklyn

Four minimal (119 - 145 residue) active site fragments of Escherichia coli Class II histidyl-tRNA synthetase were constructed, expressed as maltose-binding protein fusions, and assayed for histidine activation as fusion proteins and after TEV cleavage, using the 32PPi exchange assay. All contain …

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Mg2+-Assisted Catalysis by B. Stearothermophilus TrpRS Is Promoted by Allosteric Effects

Li Li, Laurie S. Kaguni, Violetta Weinreb, Charles W. Carter et autres

Mn2+-assisted catalysis by B. stearothermophilus TrpRS parallels that in polymerases and reduces specificity in amino acid activation. As predicted by non-equilibrium molecular dynamics simulations, multi-variant thermodynamic cycles with [ATP]-dependent Michaelis-Menten kinetics and Mn2+ for Mg2+ substitution demonstrate energetic coupling of ATP affinities …

Functional Class I and II Amino Acid-activating Enzymes Can Be Coded by Opposite Strands of the Same Gene

Katiria Gonzalez-Rivera, Luis Martínez‐Rodríguez, Srinivas Niranj Chandrasekaran, Brian Kuhlman et autres

Aminoacyl-tRNA synthetases (aaRS) catalyze both chemical steps that translate the universal genetic code. Rodin and Ohno offered an explanation for the existence of two aaRS classes, observing that codons for the most highly conserved Class I active-site residues are anticodons for corresponding …

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A Master Switch Couples Mg2+-Assisted Catalysis to Domain Motion in B. Stearothermophilus Tryptophanyl-tRNA Synthetase

Violetta Weinreb, Li Li, Charles W. Carter

We demonstrate how Tryptophanyl-tRNA synthetase (TrpRS) uses conformation-dependent Mg2+ activation to couple catalysis of tryptophan activation to specific, functional domain movements. Rate acceleration by Mg2+ requires ~ -6.0 kcal/mole in protein•Mg2+ interaction energy, none of which arises from the active site. A …

Enhanced Amino Acid Selection in Fully Evolved Tryptophanyl-tRNA Synthetase, Relative to Its Urzyme, Requires Domain Motion Sensed by the D1 Switch, a Remote Dynamic Packing Motif

Marc Delarue, Charles W. Carter, Patrice Koehl, Violetta Weinreb et autres

We previously showed (Li, L., and Carter, C. W., Jr. (2013) J. Biol. Chem. 288, 34736–34745) that increased specificity for tryptophan versus tyrosine by contemporary Bacillus stearothermophilus tryptophanyl-tRNA synthetase (TrpRS) over that of TrpRS Urzyme results entirely from coupling between the anticodon-binding …

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