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Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs by Aleksandra Luginina, Anastasiia Gusach, Egor Marin, Alexey.

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Presentation on theme: "Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs by Aleksandra Luginina, Anastasiia Gusach, Egor Marin, Alexey."— Presentation transcript:

1 Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs
by Aleksandra Luginina, Anastasiia Gusach, Egor Marin, Alexey Mishin, Rebecca Brouillette, Petr Popov, Anna Shiriaeva, Élie Besserer-Offroy, Jean-Michel Longpré, Elizaveta Lyapina, Andrii Ishchenko, Nilkanth Patel, Vitaly Polovinkin, Nadezhda Safronova, Andrey Bogorodskiy, Evelina Edelweiss, Hao Hu, Uwe Weierstall, Wei Liu, Alexander Batyuk, Valentin Gordeliy, Gye Won Han, Philippe Sarret, Vsevolod Katritch, Valentin Borshchevskiy, and Vadim Cherezov Science Volume 5(10):eaax2518 October 9, 2019 Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

2 Fig. 1 Overall structure of CysLT1R and its comparison with other receptors.
Overall structure of CysLT1R and its comparison with other receptors. (A) Side and (B) top views of CysLT1R-pran (receptor, orange; ligand, blue) and CysLT1R-zafir (receptor, green; ligand, yellow). (C) Superposition of CysLT1R-pran with BLT1-BIIL260 [Protein Data Bank (PDB) ID 5X33, light blue] and P2Y1R-BPTU (PDB ID 4XNV, pink). (D) Distribution of lipid receptors on the human GPCR sequence homology tree. CysLT1R and CysLT2R are marked as red dots, and other lipid receptors are marked as blue dots. The percentage of the lipid receptors located on each branch is shown, with the exact numbers given in parenthesis. The membrane boundaries are shown as dashed lines in (A) and (C). Aleksandra Luginina et al. Sci Adv 2019;5:eaax2518 Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

3 Fig. 2 Functional motifs of CysLT1R show unusual inactive-state features.
Functional motifs of CysLT1R show unusual inactive-state features. (A) Superposition of CysLT1R-pran (orange) with β2AR in inactive (PDB ID 2RH1; violet) and active (PDB ID 3SN6; teal) conformations. The membrane boundaries are shown as dashed lines. Loops are removed for clarity. (B to E) Zoom in on functional elements: DRY motif (B), intracellular region (C), P-I-F motif (D), and NPxxY motif (E). A different conformation of R in CysLT1R-zafir (chain A) is shown as green sticks in (B). Aleksandra Luginina et al. Sci Adv 2019;5:eaax2518 Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

4 Fig. 3 Sodium-binding pocket in CysLT1R.
Sodium-binding pocket in CysLT1R. (A) Details of Na+ (purple sphere) coordination. Water molecule is shown as a red sphere. (B) Comparison of all high-resolution GPCR structures with resolved Na+. Sodium ions are shown as purple spheres for the δ-branch receptors: CysLT1R-zafir (green), PAR1 (light purple; PDB ID 3VW7), PAR2 (PDB ID 5NDD), and as yellow spheres for receptors from the α-branch: A2AAR (yellow; PDB ID 4EIY) and β1AR (turkey; PDB ID 4BVN), and the γ-branch: DOR (PDB ID 4N6H). (C and D) Frequency analysis of amino acid occurrence in the sodium pocket of the δ-branch class A GPCRs (C) and other class A receptors excluding the δ-branch (D). Yellow color marks amino acids with hydrophobic side chains; green, aromatic; red, negatively charged; blue, positively charged; purple, polar uncharged; pink, Gly and Pro. Frames indicate positions with the largest differences. The frequency analysis was performed using the weblogo.berkeley.edu server. Aleksandra Luginina et al. Sci Adv 2019;5:eaax2518 Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

5 Fig. 4 Orthosteric ligand-binding pocket in CysLT1R.
Orthosteric ligand-binding pocket in CysLT1R. (A and D) Details of ligand-receptor interactions for pranlukast (A) and zafirlukast (D). (B and E) Pocket shapes for pranlukast (B) and zafirlukast (E). (C and F) Pocket entrance for pranlukast, closed “gate” (C), and zafirlukast, open “gate” (F). (G and H) 2D representations of receptor-ligand interactions for pranlukast (G) and zafirlukast (H). Water molecules are shown as red spheres in (A). Residues engaged in the same type of interactions with both zafirlukast and pranlukast are colored in light green, and those engaged in different types are colored in orange (G and H). The membrane boundary is shown as a dashed line in (B, C, E, and F). Aleksandra Luginina et al. Sci Adv 2019;5:eaax2518 Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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