Biology subjects

Oleinikovas, V.

Publications and source records attributed to Oleinikovas, V..

3 recordsLinked to original sources

bioRxiv2024

Mining the CRBN Target Space Redefines Rules for Molecular Glue-induced Neosubstrate Recognition

The CRL4CRBN ubiquitin ligase is leveraged by molecular glue degraders, small molecules that reprogram ligase specificity to induce degradation of clinically relevant neosubstrate proteins. Known CRBN neosubstrates share a generalizable {beta}-hairpin G-loop recognition motif, yet systematic exploration of the CRBN target landscape is still pending. Through computational mining of the human proteome using structure-based approaches, we predict over 1,400 CRBN-compatible {beta}-hairpin G-loop proteins across diverse target classes, identify novel mechanisms of neosubstrate recognition through structurally differentiated helical motifs and molecular surface mimicry, and validate 22 representative neosubstrates with clinical implications. This work broadens the CRBN target space, redefines rules for neosubstrate recognition and establishes a platform for the elimination of challenging drug targets by repurposing CRL4CRBN through next-generation molecular glue degraders.

biochemistry↗

bioRxiv2024

PLINDER: The protein-ligand interactions dataset and evaluation resource

Protein-ligand interactions (PLI) are foundational to small molecule drug design. With computational methods striving towards experimental accuracy, there is a critical demand for a well-curated and diverse PLI dataset. Existing datasets are often limited in size and diversity, and commonly used evaluation sets suffer from training information leakage, hindering the realistic assessment of method generalization capabilities. To address these shortcomings, we present PLIN-DER, the largest and most annotated dataset to date, comprising 449,383 PLI systems, each with over 500 annotations, similarity metrics at protein, pocket, interaction and ligand levels, and paired unbound (apo) and predicted structures. We propose an approach to generate training and evaluation splits that minimizes task-specific leakage and maximizes test set quality, and compare the resulting performance of DiffDock when retrained with different kinds of splits.

biochemistry↗

bioRxiv2020

The allosteric modulation of Complement C5 by knob domain peptides

To overcome limited germline combinatorial diversity, bovines have evolved a subset of antibodies with ultra-long CDRH3 regions that harbour cysteine-rich knob domains. To produce affinity-maturated peptides, we previously isolated autonomous 3-6 kDa knob domains from bovine antibodies. Here, we show that binding of four knob domain peptides elicits a range of effects on the clinically validated drug target complement C5. Allosteric mechanisms predominated, with one peptide selectively inhibiting C5 cleavage by the alternative pathway C5 convertase, revealing a targetable mechanistic difference between the classical and alternative pathway C5 convertases. Taking a hybrid biophysical approach, we present C5-knob domain co-crystal structures and, by solution methods, observed allosteric effects propagating >50 [A] from the binding sites. This study expands the therapeutic scope of C5, presents new inhibitors and introduces knob domains as new, low molecular weight antibody fragments, with therapeutic potential.

immunology↗