Biology subjects

Merski, M.

Publications and source records attributed to Merski, M..

4 recordsLinked to original sources

bioRxiv2024

GPCRVS - AI-driven decision support system for GPCR virtual screening

SummaryG protein-coupled receptors (GPCRs) constitute the largest and most frequently used family of molecular drug targets. The simplicity of GPCR drug design results from their common seven-transmembrane helix topology and well-understood signaling pathways. GPCRs are extremely sensitive to slight changes in the chemical structure of compounds, which allows for the reliable design of highly selective and specific drugs. Only recently has the number of GPCR structures, both in their active and inactive conformations together with their active ligands, become sufficient to comprehensively apply machine learning in decision support systems to predict compound activity for drug design. Here, we describe GPCRVS, an efficient machine learning web service for the online assessment of compound activity against several GPCR targets, including peptide and protein-binding GPCRs, the most difficult for virtual screening tasks. As a decision support system, GPCRVS evaluates compounds in terms of their activity range, the pharmacological effect they exert on the receptor, and the binding modes they could possibly demonstrate for certain types of GPCR receptors. GPCRVS can be applied to compounds ranging from small molecules to short peptides uploaded as common chemical format files. The activity class assignment and the binding affinity prediction are provided in a reference to similar predictions precomputed for already known active ligands of each GPCR target. This multiclass classification in GPCRVS, handling often incomplete and fuzzy biological data, was validated on ChEMBL-retrieved data sets for secretin-like and chemokine GPCR receptors. Availability and ImplementationGPCRVS is freely available at: https://gpcrvs.chem.uw.edu.pl

pharmacology and toxicology↗

bioRxiv2024

Human FASTK preferentially binds single-stranded and G-rich RNA

Fas-activated serine/threonine kinase (FASTK) is the founding member of the FASTKD protein family, which was shown to regulate the fate of mRNA molecules on multiple levels. The mitochondrial variant of FASTK co-localizes with mitochondrial RNA granules and regulates degradation of mitochondrial mRNAs, whereas the cytoplasmic and nuclear forms of FAST are involved in regulation of alternative splicing, cytoplasmic RNA granule formation and mRNA translation. Despite these multiple roles of FASTK in mRNA biology, the exact rules of RNA recognition by this protein remained undetermined. Here, we demonstrate direct RNA binding by purified human FASTK and show its preference for single-stranded G-rich sites and RNA G-quadruplexes. Addition of FASTK alone was sufficient to achieve protection of mitochondrial mRNAs from degradation by the degradosome. Structural characterization by SAXS showed that FASTK in solution is a monomer with an extended conformation. Point mutagenesis studies supported the structural predictions of an exposed RNA-binding interface in the central helical region, preceded by a smaller, flexibly attached, helical N-terminal domain. We provide the first such extensive in vitro characterization of the RNA binding properties for a representative of the FASTKD protein family, and suggest how these intrinsic properties may underly FASTK function in mRNA metabolism.

molecular biology↗

bioRxiv2022

The Repeating, Modular Architecture of the HtrA Proteases

A conserved, 26 residue sequence [AA(X2)[A/G][G/L](X2)GDV[I/L](X2)[V/L]NGE(X1)V(X6)] and corresponding structure repeating module was identified within the HtrA protease family using a non-redundant set (N=20) of publically available structures. While the repeats themselves were far from sequence perfect they had notable conservation to a statistically significant level with three or more repetitions identified within one protein at a level that would be expected to randomly occur only once per 1031 residues. This sequence repeat was associated with a six stranded antiparallel {beta}-barrel module, two of which are present in the core of the structures of the PA clan of serine proteases, while a modified version of this module could be identified in the PDZ-like domains. Automated structural alignment methods had difficulties in superimposing these {beta}-barrels but use of a target human HtrA2 structure showed that these modules had an average RMSD across the set of structures of less than 2 [A] (mean and median). Our findings support Dayhoffs hypothesis that complex proteins arose through duplication of simpler peptide motifs and domains.

bioinformatics↗

bioRxiv2021

Thiamin-Diphosphate Enzymes Are an Ancient Family of Repeat Proteins

A repeating sequence and structure pattern that is highly similar to the canonical cofactor binding motif has been identified in the thiamin-diphosphate dependent (ThDP) enzyme family. We have identified more than a thousand of these repeats in a non-redundant set (N = 58) of ThDP enzyme structures. The repeating element has a helix-turn-strand secondary structure which typically begins with an [G/A]{X(1,2)}[G/A] sequence motif with a typical length of 29 residues. The catalytically important diphosphate and aminopyrimidine interacting domains are comprised of a set of six of these repeats in a conserved architecture with a flavodoxin-like 213465 strand order. The canonical ThDP binding motif is the fourth repeat in the ThDP binding domain, while the conserved aminopyrimidine interacting glutamate is part of the second repeat in its domain. The third and fourth repeats form a contact between the functional domains, while the fifth repeat in the N-terminal domain forms an inter-chain contact. The conservation of these functional properties highlights the role of these repeats in the function and structure of this well-studied enzyme family and agrees with the principle of modular assembly in protein ancestry.

biophysics↗