5WQC

Crystal structure of human orexin 2 receptor bound to the selective antagonist EMPA determined by the synchrotron light source at SPring-8.

Summary for 5WQC

• Entry DOI: 10.2210/pdb5wqc/pdb
• Descriptor: Orexin receptor type 2,GlgA glycogen synthase,Orexin receptor type 2, N-ethyl-2-[(6-methoxypyridin-3-yl)-(2-methylphenyl)sulfonyl-amino]-N-(pyridin-3-ylmethyl)ethanamide, OLEIC ACID, ... (5 entities in total)
• Functional Keywords: g protein-coupled receptor, orexin neurotransmitters, orexin 2 receptor, orexin-a, orexin-b, empa, n-linked glycosylation, signaling protein
• Biological source: Homo sapiens (Human); More
• Cellular location: Cell membrane ; Multi- pass membrane protein : O43614
• Total number of polymer chains: 1
• Total formula weight: 66310.00

Authors

Suno, R.,Hirata, K.,Yamashita, K.,Tsujimoto, H.,Sasanuma, M.,Horita, S.,Yamamoto, M.,Rosenbaum, D.M.,Iwata, S.,Shimamura, T.,Kobayashi, T. (deposition date: 2016-11-25, release date: 2017-11-29, Last modification date: 2024-11-13)

Primary citation

Suno, R.,Kimura, K.T.,Nakane, T.,Yamashita, K.,Wang, J.,Fujiwara, T.,Yamanaka, Y.,Im, D.,Horita, S.,Tsujimoto, H.,Tawaramoto, M.S.,Hirokawa, T.,Nango, E.,Tono, K.,Kameshima, T.,Hatsui, T.,Joti, Y.,Yabashi, M.,Shimamoto, K.,Yamamoto, M.,Rosenbaum, D.M.,Iwata, S.,Shimamura, T.,Kobayashi, T.
Crystal Structures of Human Orexin 2 Receptor Bound to the Subtype-Selective Antagonist EMPA
Structure, 26:7-19.e5, 2018

PubMed Abstract: Orexin peptides in the brain regulate physiological functions such as the sleep-wake cycle, and are thus drug targets for the treatment of insomnia. Using serial femtosecond crystallography and multi-crystal data collection with a synchrotron light source, we determined structures of human orexin 2 receptor in complex with the subtype-selective antagonist EMPA (N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide) at 2.30-Å and 1.96-Å resolution. In comparison with the non-subtype-selective antagonist suvorexant, EMPA contacted fewer residues through hydrogen bonds at the orthosteric site, explaining the faster dissociation rate. Comparisons among these OXR structures in complex with selective antagonists and previously determined OXR/OXR structures bound to non-selective antagonists revealed that the residue at positions 2.61 and 3.33 were critical for the antagonist selectivity in OXR. The importance of these residues for binding selectivity to OXR was also revealed by molecular dynamics simulation. These results should facilitate the development of antagonists for orexin receptors.

PubMed: 29225076
DOI: 10.1016/j.str.2017.11.005

Experimental method

X-RAY DIFFRACTION (1.96 Å)