Laboratory of ligand-receptor interactions
Laboratory was organised in 2009 and is headed by Dr. Igor Kasheverov
The main scope of the Ligand-receptor interactions lab is structure-function relationships of natural and artificial peptide ligands of several Cys-loop receptors (nAChR, GlyR and GABAA). Construction of completely new active compounds based on known anticholinergic ligands is also in the field of our interest.
The lab conducts computer-aided design of new compounds based on diverse conotoxins of different structural classes and modelling of their complexes with nicotinic receptors (nAChR) and acetylcholine-binding proteins (AChBP). We have at our disposal eqipment for peptide synthesis, chromatography and mass-spectrometry, which is used for synthesys and characterization of active compounds. We also have electrophysiology and radioligand assay eqipment for ligans activities research.
Our lab contacts has lots of international collaborations in Germany, France, Finland, Greece, China and Vietnam. And we are open to new contacts!
Previously, more than forty diverse conotoxins analogs were synthetized and studied in the lab. Partly these studies could be represented by following reviews:
Tsetlin V., Utkin Y., Kasheverov I. (2009). Polypeptide and peptide toxins, magnifying lenses for binding sites in nicotinic acetylcholine receptors. Biochem Pharmacol. 78(7), 720—731
Kasheverov I.E., Utkin Y.N., Tsetlin V.I. (2009). Naturally occurring and synthetic peptides acting on nicotinic acetylcholine receptors. Curr Pharm Des. 15(21), 2430—2452.
|Igor' Kasheverov, D.Sc||depart. firstname.lastname@example.org, |
|Maxim Zhmak, Ph.D.||s. r. email@example.com, |
|Elena Kryukova, Ph.D.||s. r. firstname.lastname@example.org, |
|Vladimir Ryabinin||s. r. f.|
|Yana Makarova||r. email@example.com, |
|Denis Kudryavtsev, Ph.D.||r. firstname.lastname@example.org|
|Igor Ivanov||r. email@example.com|
|Dmitry Lebedev||r. firstname.lastname@example.org, |
|Dmitry Kuzmin||PhD email@example.com, |
|Natalija Karamyshevafirstname.lastname@example.org, |
|Alexej Khrushev||PhD email@example.com|
Characterization of the "analgesic" conotoxins' binding sites on the nicotinic receptor and its models (2018-12-03)
A set of Cys-Cys isomers of "analgesic" conotoxins RgIA and GeXIVA acting through ortho- or allosteric binding sites of α9/α10 of nicotinic acetylcholine receptor, respectively, was synthesized. The study of them by direct or competitive radioligand analysis with water-soluble models of this receptor - acetylcholine-binding protein and recombinant extracellular domain of the α9 receptor subunit, showed that they effectively interact with the micromolar affinity only with the orthosteric binding site of these models.
- (2018). Orthosteric and/or Allosteric Binding of α-Conotoxins to Nicotinic Acetylcholine Receptors and Their Models. Mar Drugs 16 (12),
Development of a new technique based on calcium imaging and functional characterization of mutant α7/α9 nAChRs with the use of this technique. (2017-12-15)
On the basis of the calcium imaging method, we developed a new technique that allows to effectively express functionally active "problematic" subtypes of nicotinic receptors (nAChRs) in cell lines. It involves co-expressing with the appropriate receptor subtype a chaperone and a fluorescent calcium sensor Case12. This technique allowed us to obtain 6 mutant forms of α7 nAChR with selected single substitutions of amino acid residues from α9 nAChR subtype. All the mutants together with the wild-type receptors were analyzed for affinity to acetylcholine and epibatidine using the developed technique. This helped to identify two key mutations - L119D and F187S which are responsible for selectivity of these nAChR subtypes to above-mentioned ligands. Computer simulations showed a significant change in the arrangement of ligands’ molecules in binding sites of these two mutant forms of the receptor, explaining the data obtained.
- (2017). Calcium imaging with genetically encoded sensor Case12: Facile analysis of α7/α9 nAChR mutants. PLoS One 12 (8), e0181936
SLURP-1 (81 amino-acid residues, 5 disulfides), identical in the amino-acid sequence to the endogenous human protein, has been synthesized and shown to differ from all known recombinant (2017-12-15)
SLURP-1 (81 amino acid residues, 5 disulfides) has been synthesized with the amino acid sequence identical to that of the endogenous human toxin-like protein. 1H-NMR revealed the same structure as in the recombinant rSLURP-1 bearing additional N-terminal Met0. These proteins have some differences in molecular dynamics, but differ greatly in their activity towards distinct subtypes of nicotinic receptors. Our work in general stresses the necessity of maximal approach to the structure of naturally-occurring proteins to solve the mechanisms of their endogenous activities and choosing appropriate medical applications.
- (2018). Interaction of Synthetic Human SLURP-1 with the Nicotinic Acetylcholine Receptors. Sci Rep 7 (1), 16606