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. 2022 Feb 17;12:2691. doi: 10.1038/s41598-022-06591-z

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© The Author(s) 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Two predicted tunnels in TAAR9 are considered as pathways for ligand entry. (a) Surface (translucent, colored by residue charge) of orthosteric binding pocket (red dotted circle) in side view (left) and extracellular view (right) are located in the center of TMs. D112^3.32, one of the critical binding sites, is in the center of pocket. (b) The location of Tunnel 1 (green) and Tunnel 2 (yellow) in TAAR9. Tunnel 1 and Tunnel 2, which originates from different parts of extracellular regions, converge at the known orthosteric binding site, D112^3.32. The salt bridge between E294^7.36 and R92^2.64 delineates the barrier between Tunnel 1 and Tunnel 2. (c) Snake plot for TAAR9 modified from GPCRdb (https://www.gpcrdb.org)^58,59 demonstrates residues around Tunnel 1 (green), Tunnel 2 (yellow), and both tunnels (cyan). All of the residues are located at the extracellular side of the most conserved residues of each helix (pink), defined as X.50 (X represents TM) on the basis of Ballesteros–Weinstein numbering scheme¹³. (d) Properties (length, radius, hydropathy, and charge) of Tunnel 1 (upper) and Tunnel 2 (lower). Both tunnels are hydrophobic (yellow) in internal regions (distance from 0 Å) near the orthosteric binding site, D112^3.32. Both hydropathy and charge show a distinct pattern between the middle and terminal of the tunnels. Both tunnels are hydrophilic in middle and hydrophobic or neutral in terminals. Distribution of charged residues shows negative charged residues (D112^3.32, E294^7.36, D281^6.58, and E179 in ECL2) in two side and positive charged R92^2.64 in the middle of both tunnels. Distance, distance (Å) to inside terminal of tunnels. Radius, radius of sphere within tunnel limited by three closest atoms. Free Radius, radius of sphere within tunnel limited by three closest main atoms in order to allow sidechain flexibility. Hydropathy index of amino acid⁶⁰, ranging from the most hydrophilic (Arg = − 4.5) to the most hydrophobic (Ile = 4.5). Charge index of amino acid is summation of the charged residues, with arginine, histidine, and lysine as + 1, and aspartic acid and glutamic acid as − 1.