TY - JOUR AU - Sarkar, Arijit AU - Mitra, Argha AU - Borics, Attila TI - All-Atom Molecular Dynamics Simulations Indicated the Involvement of a Conserved Polar Signaling Channel in the Activation Mechanism of the Type I Cannabinoid Receptor JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 4 PG - 18 SN - 1661-6596 DO - 10.3390/ijms24044232 UR - https://m2.mtmt.hu/api/publication/33723346 ID - 33723346 AB - The type I cannabinoid G protein-coupled receptor (CB1, GPCR) is an intensely investigated pharmacological target, owing to its involvement in numerous physiological functions as well as pathological processes such as cancers, neurodegenerative diseases, metabolic disorders and neuropathic pain. In order to develop modern medications that exert their effects through binding to the CB1 receptor, it is essential to understand the structural mechanism of activation of this protein. The pool of atomic resolution experimental structures of GPCRs has been expanding rapidly in the past decade, providing invaluable information about the function of these receptors. According to the current state of the art, the activity of GPCRs involves structurally distinct, dynamically interconverting functional states and the activation is controlled by a cascade of interconnecting conformational switches in the transmembrane domain. A current challenge is to uncover how different functional states are activated and what specific ligand properties are responsible for the selectivity towards those different functional states. Our recent studies of the mu-opioid and beta(2)-adrenergic receptors (MOP and beta(2)AR, respectively) revealed that the orthosteric binding pockets and the intracellular surfaces of these receptors are connected through a channel of highly conserved polar amino acids whose dynamic motions are in high correlation in the agonist- and G protein-bound active states. This and independent literature data led us to hypothesize that, in addition to consecutive conformational transitions, a shift of macroscopic polarization takes place in the transmembrane domain, which is furnished by the rearrangement of polar species through their concerted movements. Here, we examined the CB1 receptor signaling complexes utilizing microsecond scale, all-atom molecular dynamics (MD) simulations in order to see if our previous assumptions could be applied to the CB1 receptor too. Apart from the identification of the previously proposed general features of the activation mechanism, several specific properties of the CB1 have been indicated that could possibly be associated with the signaling profile of this receptor. LA - English DB - MTMT ER - TY - JOUR AU - Mitra, Argha AU - Sarkar, Arijit AU - Borics, Attila TI - Universal Properties and Specificities of the beta(2)-Adrenergic Receptor-G(s) Protein Complex Activation Mechanism Revealed by All-Atom Molecular Dynamics Simulations JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 22 PY - 2021 IS - 19 PG - 19 SN - 1661-6596 DO - 10.3390/ijms221910423 UR - https://m2.mtmt.hu/api/publication/32473848 ID - 32473848 N1 - Funding Agency and Grant Number: 'Stipendium Hungaricum' program of the Hungarian Ministry of Foreign Affairs and Trade; Tempus Public Foundation Funding text: Scholarship for A.S. was provided by the 'Stipendium Hungaricum' program of the Hungarian Ministry of Foreign Affairs and Trade and the Tempus Public Foundation. AB - G protein-coupled receptors (GPCRs) are transmembrane proteins of high pharmacological relevance. It has been proposed that their activity is linked to structurally distinct, dynamically interconverting functional states and the process of activation relies on an interconnecting network of conformational switches in the transmembrane domain. However, it is yet to be uncovered how ligands with different extents of functional effect exert their actions. According to our recent hypothesis, based on indirect observations and the literature data, the transmission of the external stimulus to the intracellular surface is accompanied by the shift of macroscopic polarization in the transmembrane domain, furnished by concerted movements of highly conserved polar motifs and the rearrangement of polar species. In this follow-up study, we have examined the beta(2)-adrenergic receptor (beta(2)AR) to see if our hypothesis drawn from an extensive study of the mu-opioid receptor (MOP) is fundamental and directly transferable to other class A GPCRs. We have found that there are some general similarities between the two receptors, in agreement with previous studies, and there are some receptor-specific differences that could be associated with different signaling pathways. LA - English DB - MTMT ER - TY - JOUR AU - Mitra, Argha AU - Sarkar, Arijit AU - Szabó, Márton Richárd AU - Borics, Attila TI - Correlated Motions of Conserved Polar Motifs Lay out a Plausible Mechanism of G Protein-Coupled Receptor Activation JF - BIOMOLECULES J2 - BIOMOLECULES VL - 11 PY - 2021 IS - 5 PG - 16 SN - 2218-273X DO - 10.3390/biom11050670 UR - https://m2.mtmt.hu/api/publication/32048186 ID - 32048186 AB - Recent advancements in the field of experimental structural biology have provided high-resolution structures of active and inactive state G protein-coupled receptors (GPCRs), a highly important pharmaceutical target family, but the process of transition between these states is poorly understood. According to the current theory, GPCRs exist in structurally distinct, dynamically interconverting functional states of which populations are shifted upon binding of ligands and intracellular signaling proteins. However, explanation of the activation mechanism, on an entirely structural basis, gets complicated when multiple activation pathways and active receptor states are considered. Our unbiased, atomistic molecular dynamics simulations of the mu opioid receptor (MOP) revealed that transmission of external stimulus to the intracellular surface of the receptor is accompanied by subtle, concerted movements of highly conserved polar amino acid side chains along the 7th transmembrane helix. This may entail the rearrangement of polar species and the shift of macroscopic polarization in the transmembrane domain, triggered by agonist binding. Based on our observations and numerous independent indications, we suggest amending the widely accepted theory that the initiation event of GPCR activation is the shift of macroscopic polarization between the ortho- and allosteric binding pockets and the intracellular G protein-binding interface. LA - English DB - MTMT ER - TY - JOUR AU - Sarkar, Arijit AU - Adamska-Bartlomiejczyk, Anna AU - Piekielna-Ciesielska, Justyna AU - Wtorek, Karol AU - Kluczyk, Alicja AU - Borics, Attila AU - Janecka, Anna TI - Design, Synthesis and Functional Analysis of Cyclic Opioid Peptides with Dmt-Tic Pharmacophore JF - MOLECULES J2 - MOLECULES VL - 25 PY - 2020 IS - 18 SN - 1420-3049 DO - 10.3390/molecules25184260 UR - https://m2.mtmt.hu/api/publication/31655071 ID - 31655071 N1 - Laboratory of Chemical Biology, United States Institute of Biochemistry, Biological Research Centre, 62. Temesvári krt., Szeged, H-6726, Hungary Theoretical Medicine Doctoral School, Hungary Faculty of Medicine, University of Szeged, 97. Tisza L. krt., Szeged, H-6722, Hungary Department of Biomolecular Chemistry, Poland Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, Lodz, 92-215, Poland Faculty of Chemistry, Poland University of Wroclaw, F. Joliot-Curie 14, Wroclaw, 50-383, Poland Export Date: 25 May 2021 CODEN: MOLEF Correspondence Address: Janecka, A.; Department of Biomolecular ChemistryPoland; email: anna.janecka@umed.lodz.pl AB - The opioid receptors are members of the G-protein-coupled receptor (GPCR) family and are known to modulate a variety of biological functions, including pain perception. Despite considerable advances, the mechanisms by which opioid agonists and antagonists interact with their receptors and exert their effect are still not completely understood. In this report, six new hybrids of the Dmt-Tic pharmacophore and cyclic peptides, which were shown before to have a high affinity for the mu-opioid receptor (MOR) were synthesized and characterized pharmacologically in calcium mobilization functional assays. All obtained ligands turned out to be selective antagonists of the delta-opioid receptor (DOR) and did not activate or block the MOR. The three-dimensional structural determinants responsible for the DOR antagonist properties of these analogs were further investigated by docking studies. The results indicate that these compounds attach to the DOR in a slightly different orientation with respect to the Dmt-Tic pharmacophore than Dmt-Tic psi[CH2-NH]Phe-Phe-NH2 (DIPP-NH2[psi]), a prototypical DOR antagonist peptide. Key pharmacophoric contacts between the DOR and the ligands were maintained through an analogous spatial arrangement of pharmacophores, which could provide an explanation for the predicted high-affinity binding and the experimentally observed functional properties of the novel synthetic ligands. LA - English DB - MTMT ER -