biochemistry papers | Gist.Science

Uncovering Functional Distant Mutations by Ultra-High-Throughput Screening of Dehalogenases

By employing ultrahigh-throughput fluorescence-activated droplet sorting with a bulky fluorogenic substrate, researchers successfully identified distal mutations in the enzyme LinB that enhance catalytic efficiency and alter specificity by modulating conformational dynamics and substrate access, demonstrating a powerful approach to uncovering functional adaptations difficult to predict through rational design.

Faldynova, H., Kovar, D., Jain, A. + 28 more2026-03-26⚗️ biochemistry

Chiral methionine oxidation reagents reveal stereospecific proteome modifications

This study introduces enantiomeric oxaziridine reagents to map stereospecific methionine oxidation sites across proteomes, demonstrating that chiral regulation of these modifications can allosterically inhibit protein function and amplify specific oxidative stress responses.

Gonzalez-Valero, A., Page, A. C. S., Bertoch, J. M. + 17 more2026-03-26⚗️ biochemistry

Integrative Structural Modeling of Intrinsically Disordered Regions in a Human HDAC2 Chromatin Remodeling Complex

This study overcomes the limitations of standard computational tools like AlphaFold in modeling intrinsically disordered regions by employing an integrative approach that combines experimental crosslinking with multiple modeling techniques to elucidate the structural assembly of the human HDAC2:MIER1:MHAP1 chromatin remodeling complex.

Nde, J., Kempf, C., Zimmermann, R. + 5 more2026-03-25⚗️ biochemistry

Structural, biophysical, and virological mechanistic characterization of HIV-1 capsid-targeting antivirals

This study demonstrates that specific chemical modifications at the R1 and R3 positions of the HIV-1 capsid inhibitor PF74 yield novel antivirals with enhanced potency, stability, and binding affinity, offering valuable insights for designing future clinical candidates.

Kirby, K. A., McFadden, W. M., Wang, L. + 18 more2026-03-25⚗️ biochemistry

A comparative investigation of the mannose binding interface in DC-SIGN and MRC1 carbohydrate recognition domains with all-atom molecular dynamics simulations

This study employs all-atom molecular dynamics simulations to reveal how specific mannose binding states accessible in the MRC1 receptor but not in the overexpressed DC-SIGN receptor explain their differing affinities, thereby providing critical insights for designing selective mannose-based therapeutics for retinoblastoma.

Geissler, S., Sacquin-Mora, S.2026-03-25⚗️ biochemistry

Multi-Objective Engineering of Fibrin-Selective Thrombolytic Proteases with Enhanced Biocatalytic Efficiency and Inhibition Resistance

This study presents a multi-objective engineering framework that successfully designed Brnoteplase, a next-generation thrombolytic protease with enhanced fibrin selectivity, inhibition resistance, and catalytic efficiency, demonstrating superior therapeutic efficacy and safety in vivo compared to current FDA-approved variants.

Toul, M., Slonkova, V., Mican, J. + 18 more2026-03-25⚗️ biochemistry

Discovery of a FANCD2-interacting protein motif (DIP-box) linking DNA Damage Response processes

This study identifies a conserved acidic region in FANCD2, termed the DIP-box, which directly binds a short linear motif in various DNA repair, histone modification, and RNA processing proteins, thereby establishing FANCD2 as a central structural hub for coordinating the DNA damage response to interstrand crosslinks.

Cao, Z., Briola, G. R., Ionita, C. + 3 more2026-03-25⚗️ biochemistry

Strand-independent degradation of uncoupled forks by EXO1 activates ATR and restrains synthesis

Using Xenopus egg extracts, this study demonstrates that EXO1 selectively degrades the 5' ends of nascent DNA at uncoupled replication forks to activate the ATR checkpoint and restrain fork progression, while leaving the 3' leading strand ends stable.

Grogan, E. J., Ozua, O. E., Kavlashvili, T. + 2 more2026-03-25⚗️ biochemistry

Structural and cellular insights into the inhibition of the drug efflux activity of the HEDGEHOG receptor PATCHED1

This study elucidates the structural and cellular mechanisms by which the inhibitor PAH blocks the drug-efflux activity of the overexpressed Hedgehog receptor PTCH1, revealing that PAH occupies a cholesterol-binding hydrophobic cavity to prevent doxorubicin transport and offering a structural roadmap for developing next-generation chemotherapeutic adjuvants.

Houha, O., Wachich, M., Debarnot, C. + 4 more2026-03-25⚗️ biochemistry

Structural dynamics between Argonaute-2 and CK1α promote target RNA release in microRNA-mediated silencing

This study reveals that the progressive base-pairing of miRNA with target RNA induces conformational changes in human Ago2, specifically moving the PAZ domain to create a binding interface for CK1α, which phosphorylates the EI region to unwind the guide-target complex and facilitate efficient RISC turnover.

Garg, A., Braviner, L., Axhemi, A. + 2 more2026-03-25⚗️ biochemistry

c-di-AMP inactivates a K+/H+ antiporter in Bacillus subtilis

This study reveals that the second messenger c-di-AMP directly inactivates the K+/H+ antiporter CpaA in *Bacillus subtilis* by binding to its RCK domain, thereby challenging previous assumptions about the simplicity of c-di-AMP's regulation of bacterial potassium homeostasis.

Figueiredo-Costa, I. R., Lorga-Gomes, M. M., Sousa-Moreira, S. C. + 2 more2026-03-25⚗️ biochemistry

Highly Stable Mn(V)-Nitrido and Nitrogen-Atom Transfer Reactivity within a De Novo Protein

This study reports the first successful creation of a highly stable, high-valent Mn(V)-nitrido complex within a de novo designed protein scaffold, which suppresses bimolecular decay and enables enantioselective catalytic aziridination via nitrogen-atom transfer.

Thomas, J., Yadav, S., Oyala, P. H. + 3 more2026-03-25⚗️ biochemistry

Enhanced RNA Formation Under Amine-Rich Local Atmospheres from 2',3'- Cyclic Nucleotides

This study demonstrates that ammonium and alkylammonium counterions significantly enhance the dry-state polymerization of 2',3'-cyclic nucleotides into RNA oligomers through hydrogen bonding, general base catalysis, and anhydrous salt formation, suggesting that ammonia-rich environments from pyrolyzed organic tars could have facilitated early RNA evolution.

Schmid, A., Kovarik, A., Hintz, J. + 12 more2026-03-25⚗️ biochemistry

Hydration and hydrolysis define antibiotic resistance conferred by macrolide esterases

This study elucidates the structural and kinetic mechanisms of four diverse Est-type macrolide esterases, revealing that a water-cage-mediated promiscuous binding and imprecise positioning dictate their substrate specificity and antibiotic resistance, offering critical insights for developing next-generation antibiotics.

Kelly, E. T. R., Myziuk, I., Hemmings, M. Z. + 4 more2026-03-25⚗️ biochemistry

Plasmin-mediated cleavage of GPIbα contributes to breakdown of platelet-von Willebrand factor complexes

This study demonstrates that while plasmin-mediated cleavage of GPIbα disrupts platelet-von Willebrand factor complexes in vitro by reducing platelet binding capacity, its role in breaking down these complexes in vivo during thrombotic thrombocytopenic purpura appears limited.

Frunt, R., Moesker, E. I., Sakai, K. + 4 more2026-03-25⚗️ biochemistry

Structure of human aldehyde oxidase under tris(2-carboxyethyl)phosphine-reducing conditions

This study demonstrates that replacing the inactivating reducing agent dithiothreitol (DTT) with tris(2-carboxyethyl)phosphine (TCEP) enables the crystallization of active human aldehyde oxidase in a new orthorhombic form, thereby overcoming previous limitations and facilitating future time-resolved crystallographic applications.

Videira, C., Esmaeeli, M., Leimkuhler, S. + 2 more2026-03-25⚗️ biochemistry

Quaternary structure and activity of glutamate dehydrogenase are regulated by reversible S-palmitoylation and mitochondrial acyl-protein thioesterases.

This study reveals that glutamate dehydrogenase (GDH) activity and hexameric assembly are reversibly regulated by S-palmitoylation at specific cysteine residues, which inhibits the enzyme by disrupting its quaternary structure, while mitochondrial thioesterases APT1 and ABHD10 restore its active form by removing the lipid modification.

Salsaa, M., Huynh, H. T. A., Dixon, C. L. + 4 more2026-03-25⚗️ biochemistry

A human cell-free translation screen identifies the NT-2 mycotoxin as a ribosomal inhibitor that binds the peptidyl transferase center

This study establishes a human cell-free high-throughput screening platform to identify the NT-2 mycotoxin as a novel ribosomal inhibitor that binds the peptidyl transferase center and induces a dormant state in mammalian protein synthesis.

Schwaller, N., Andenmatten, D., Luginbuehl, J. + 6 more2026-03-24⚗️ biochemistry

A crucial role for PIH1D1 in modulating p53 stability via the R2TP complex

This study reveals that the R2TP complex, specifically through the PIH1D1 subunit, stabilizes p53 to regulate the cell cycle, offering a potential therapeutic strategy for restoring p53 function in cancer cells.

Singh, D. K., Akhtar, Q., Mir, R. A.2026-03-24⚗️ biochemistry

FoTO1 orchestrates Taxol biosynthesis through catalytic and non-catalytic mechanisms

This study reveals that FoTO1 orchestrates early Taxol biosynthesis through a dual mechanism, acting both as a catalytic enzyme converting taxadiene-(4),5-epoxide to taxadien-5-ol and as a non-catalytic scaffold that organizes P450 enzymes to enhance metabolic flux across plastid and ER compartments.

Wick, C., Somani, A., Liu, J. + 5 more2026-03-24⚗️ biochemistry

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