Secreted Isoform of Human Lynx1 (SLURP-2): Spatial Structure and Pharmacology of Interactions with Different Types of Acetylcholine Receptors

Lyukmanova E. N.; Shulepko M. A.; Shenkarev Z. O.; Bychkov M. L.; Paramonov A. S.; Chugunov A. O.; Kulbatskii D. S.; Arvaniti M.; Dolejsi E.; Schaer T.; Arseniev A. S.; R. Efremov; Thomsen M. S.; Dolezal V.; Bertrand D.; Dolgikh D. A.; Kirpichnikov M. P.

doi:10.1038/srep30698

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Secreted Isoform of Human Lynx1 (SLURP-2): Spatial Structure and Pharmacology of Interactions with Different Types of Acetylcholine Receptors

Scientific Reports. 2016. Vol. 6. No. 30698. P. 1–17.

Lyukmanova E. N., Shulepko M. A., Shenkarev Z. O., Bychkov M. L., Paramonov A. S., Chugunov A. O., Kulbatskii D. S., Arvaniti M., Dolejsi E., Schaer T., Arseniev A. S., Efremov R., Thomsen M. S., Dolezal V., Bertrand D., Dolgikh D. A., Kirpichnikov M. P.

Human-secreted Ly-6/uPAR-related protein-2 (SLURP-2) regulates the growth and differentiation of epithelial cells. Previously, the auto/paracrine activity of SLURP-2 was considered to be mediated via its interaction with the α3β2 subtype of the nicotinic acetylcholine receptors (nAChRs). Here, we describe the structure and pharmacology of a recombinant analogue of SLURP-2. Nuclear magnetic resonance spectroscopy revealed a three-finger' fold of SLURP-2 with a conserved β-structural core and three protruding loops. Affinity purification using cortical extracts revealed that SLURP-2 could interact with the α3, α4, α5, α7, β2, and β4 nAChR subunits, revealing its broader pharmacological profile. SLURP-2 inhibits acetylcholine-evoked currents at α4β2 and α3β2-nAChRs (IC 50 ∼0.17 and >3 μM, respectively) expressed in Xenopus oocytes. In contrast, at α7-nAChRs, SLURP-2 significantly enhances acetylcholine-evoked currents at concentrations <1 μM but induces inhibition at higher concentrations. SLURP-2 allosterically interacts with human M1 and M3 muscarinic acetylcholine receptors (mAChRs) that are overexpressed in CHO cells. SLURP-2 was found to promote the proliferation of human oral keratinocytes via interactions with α3β2-nAChRs, while it inhibited cell growth via α7-nAChRs. SLURP-2/mAChRs interactions are also probably involved in the control of keratinocyte growth. Computer modeling revealed possible SLURP-2 binding to the classical' orthosteric agonist/antagonist binding sites at α7 and α3β2-nAChRs.

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Keywords: nicotinic acetylcholine receptor никотиновый ацетилхолиновый рецептор computer modeling and simulation Human-secreted Ly-6/uPAR-related protein-2 (SLURP-2)белок SLURP-2 компьютерное молекулярное моделирование

Add-Ons To Molecular Modeling Methods: Improvement In Activity Prediction

Svitanko I. V., Novikov F. N., Medvedev M. G., , in: XXII Mendeleev Congress on General and Applied Chemistry, October 7-12, 2024, Federal Territory “Sirius”, Russia. Book of abstracts in 7 volumesVol. 5.: “Admiral Print” LLC, 2024.

ADD-ONS TO MOLECULAR MODELING METHODS: IMPROVEMENT IN ACTIVITY PREDICTION ...

Added: October 14, 2024

Molecular Dynamics Simulations of Nucleosomes Are Coming of Age

Fedulova A., Armeev G., Romanova T. et al., Wiley Interdisciplinary Reviews: Computational Molecular Science 2024 Vol. 14 No. 4 Article e1728

Understanding the function of eukaryotic genomes, including the human genome, is undoubtedly one of the major scientific challenges of the 21st century. The cornerstone of eukaryotic genome organization is nucleosomes—elementary building blocks of chromatin about 10 nm in size that wrap DNA around an octamer of histone proteins. Nucleosomes are integral players in all genomic processes, ...

Added: August 29, 2024

Imidazole-4-N-acetamide Derivatives as a Novel Scaffold for Selective Targeting of Cyclin Dependent Kinases

Rusina P., Gandalipov E., Abdyusheva Y. et al., Cancers 2023 Vol. 15 No. 15 Article 3766

General toxicity for the organism is a major drawback of anticancer drugs. Development of new generation chemotherapeutics requires the knowledge about macromolecules critical for tumor cell viability. Among these species (called therapeutic targets), the protein kinases are the established enzymes. However, the parts of protein kinases that are supposed to be targeted by drugs can ...

Added: November 1, 2023

Proceedings of the Conference on Modeling and Analysis of Complex Systems and Processes 2021 (MACSPro 2021)

Aachen: CEUR Workshop Proceedings, 2022.

Added: February 6, 2022

Computational modeling and target synthesis of monomethoxy-substituted o-diphenylisoxazoles with unexpectedly high antimitotic microtubule destabilizing activity

Stroylov Viktor S., Svitanko I., Maksimenko A. et al., Bioorganic and Medicinal Chemistry Letters 2020 Vol. 30 Article 127608

The ability of monomethoxy-substituted o-diphenylisoxazoles 2a-d to interact with the colchicine site of tubulin was predicted using computational modeling, docking studies, and calculation of binding affinity. The respective molecules were synthesized in high yields by three steps reaction using easily available benzaldehydes, acetophenones, and arylnitromethanes as starting material. The calculated antitubulin effect was confirmed in vivo in a sea urchin ...

Added: December 24, 2021

Data transfer from satellite to ground station emulator

M. A. Bubnova, V. A. Baleskin, A. N. Kosinov et al., Journal of Physics: Conference Series 2021 Vol. 2134 Article 012026

"Data transfer from satellite to ground station emulator" application has been developed for modelling data transfer between a small spacecraft at low-earth orbit and a control center on Earth. The application takes into account multiple parameters allowing to replace a number of experiments. Additionally, the SGP4 model and models such of parameters such as bit ...

Added: December 22, 2021

Biochemical basis of skin disease Mal de Meleda: SLURP-1 mutants differently affect keratinocyte proliferation and apoptosis

Shulepko M., Bychkov M., Shenkarev Z. et al., Journal of Investigative Dermatology 2021 P. 1–9

Mal de Meleda is an autosomal recessive palmoplantar keratoderma associated with mutations in a gene encoding SLURP-1. SLURP-1 controls growth, differentiation, and apoptosis of keratinocytes by interaction with α7-type nicotinic acetylcholine receptors. SLURP-1 has a three-finger structure with a β-structural core (head) and three prolonged loops (fingers). To determine the role of SLURP-1 mutations, we produced 22 mutant variants of the protein, ...

Added: May 18, 2021

Proceedings of the 32nd European Modeling & Simulation Symposium (EMSS 2020)

Dime University of Genoa, 2020.

The European Modeling and Simulation Symposium is one of the most important Simulation Appointments in Europe. As a tradition, the conference focuses on Modeling & Simulation in Industry taking into consideration both applications and theoretical approaches. The conference proposes a multi-sides perspective on the Modeling & Simulation environment. Tracks organization is intended to cover different ...

Added: September 27, 2020

Environmental and dynamic effects explain how nisin captures membrane-bound lipid II

Panina I., Krylov N., Nolde D. et al., Scientific Reports 2020 Vol. 10 Article 8821

Antibiotics (AB) resistance is a major threat to global health, thus the development of novel AB classes is urgently needed. Lantibiotics (i.e. nisin) are natural compounds that effectively control bacterial populations, yet their clinical potential is very limited. Nisin targets membrane-embedded cell wall precursor — lipid II — via capturing its pyrophosphate group (PPi), which is unlikely ...

Added: June 1, 2020

Dielectric-dependent strength of interlipid H-bonding in biomembranes: a model case study.

Efremov R., Journal of Chemical Information and Modeling 2019 Vol. 59 No. 6 P. 2765–2775

Atomistic aspects of the structural organization, dynamics, and functioning of hydrated lipid bilayers - model cell membranes - are primarily governed by the fine balance of intermolecular interactions between all constituents of these systems. Besides the hydrophobic effect, which shapes the overall skeleton of lipid membranes, very important contribution to their behavior is made by ...

Added: August 7, 2019

Specific refolding pathway of viscumin A chain in membrane-like medium reveals a possible mechanism of toxin entry into cell.

Efremov R., Нольде Д. Е., Волынский П. Е. et al., Scientific Reports 2019 Vol. 9 No. 413 P. 1–12

How is a water-soluble globular protein able to spontaneously cross a cellular membrane? It is commonly accepted that it undergoes significant structural rearrangements on the lipid-water interface, thus acquiring membrane binding and penetration ability. In this study molecular dynamics (MD) simulations have been used to explore large-scale conformational changes of the globular viscumin A chain ...

Added: February 6, 2019

Competitive Adsorption of H2O and CO2 in 2-Dimensional Nano-Confinement: GCMD Simulations of Cs- and Ca-Hectorite

Loganathan N., Bowers G. M., Yazaydin A. O. et al., Journal of Physical Chemistry C 2018 Vol. 122 No. 41 P. 23460–23469

The intercalation of H2O, CO2, and other fluid species in expandable clay minerals (smectites) may play a significant role in controlling the behavior of these species in geological C-sequestration and enhanced petroleum production and has been the subject of intensive study in recent years. This paper reports the results of a computational study of the ...

Added: October 20, 2018

Clay swelling in dry supercritical carbon dioxide: Effects of interlayer cations on the structure, dynamics, and energetics of CO2 intercalation probed by XRD, NMR and GCMD simulations.

Loganathan N., Bowers G. M., Yazaydin A. O. et al., Journal of Physical Chemistry C 2018 Vol. 122 No. 8 P. 4391–4402

In situ XRD and NMR experiments combined with molecular dynamics simulations using the grand canonical ensemble (GCMD) show that cation size, charge and solvation energy play critical roles in determining the interlayer expansion of smectite clay minerals when exposed to dry supercritical CO2 under conditions relevant to the earthâ€™s upper crust, petroleum reservoirs, and geological ...

Added: May 31, 2018

Proceedings - 31th European Conference on Modelling and Simulation, ECMS 2017

[б.и.], 2017.

Added: October 27, 2017

Structural Insight into Specificity of Interactions between Non-conventional Three-Finger Toxin WTX and Muscarinic Acetylcholine Receptors

Lyukmanova E., Shenkarev Z., Shulepko M. et al., Journal of biological chemistry 2015 Vol. 290 P. 23616–23630

Weak toxin from Naja kaouthia (WTX) belongs to the group of nonconventional “three-finger” snake neurotoxins. It irreversibly inhibits nicotinic acetylcholine receptors and allosterically interacts with muscarinic acetylcholine receptors (mAChRs). Using site-directed mutagenesis, NMR spectroscopy, and computer modeling, we investigated the recombinant mutant WTX analogue (rWTX) which, compared with the native toxin, has an additional N-terminal methionine residue. ...

Added: March 14, 2017

Central loop of non-conventional toxin WTX from Naja kaouthia is important for interaction with nicotinic acetylcholine receptors.

Lyukmanova E., Shulepko M., Shenkarev Z. et al., Toxicon 2016 Vol. 119 P. 274–279

‘Three-finger’ toxin WTX from Naja kaouthia interacts with nicotinic and muscarinic acetylcholine receptors (nAChRs and mAChRs). Mutagenesis and competition experiments with 125I-α-bungarotoxin revealed that Arg31 and Arg32 residues from the WTX loop II are important for binding to Torpedo californica and human α7 nAChRs. Computer modeling suggested that loop II occupies the orthosteric binding site at α7 nAChR. The similar ...

Added: March 14, 2017

Central loop of non-conventional toxin WTX from Naja kaouthia is important for interaction with nicotinic acetylcholine receptors

Lyukmanova E. N., Shulepko M. A., Shenkarev Z. O. et al., Toxicon 2016 Vol. 119 No. September P. 274–279

Highlights • Mutagenesis of non-conventional toxin WTX from Naja kaouthia is performed. • Activity of WTX and its mutants on muscle-type and α7-type of nAChRs was studied. • R31 and R32 from the loop II is important for binding to both types of receptors. • Modeling revealed the loop II entering into the orthosteric site of the α7 nAChRs. <hr /> Abstract ‘Three-finger’ toxin WTX from Naja kaouthia interacts with ...

Added: September 14, 2016

Enterprise and Organizational Modeling and Simulation. 11th International Workshop, EOMAS 2015, Held at CAiSE 2015, Stockholm, Sweden, June 8-9, 2015, Selected Papers

Springer, 2015.

This book constitutes the refereed proceedings of the 11th International Workshop on Enterprise and Organizational Modeling and Simulation, EOMAS 2015, held at CAiSE 2015, in June 2015 in Stockholm, Sweden. EOMAS was founded with the purpose to become a forum among researchers and practitioners to share their research and practical findings by encouraging the dissemination of research ...

Added: October 20, 2015

Рациональное конструирование новых лигандов никотиновых рецепторов на основе альфа-конотоксина PnIA

Efremov R., Кашеверов И. Е., Кудрявцев Д. С. et al., Доклады Академии наук 2015 Т. 461 № 4 С. 476–479

This work continues the previous study and is aimed at designing a more efficient ligand for α 7 nAChR using α ?conotoxin PnIA. Here, we applied the computational protein surface topography (PST) technique, developed at the Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, and for the first time used it to select the necessary mutations in conotoxins. ...

Added: July 21, 2015