4ZJC

Structures of the human OX1 orexin receptor bound to selective and dual antagonists

Summary for 4ZJC

• Entry DOI: 10.2210/pdb4zjc/pdb
• Related: 4ZJ8
• Descriptor: human OX1R fusion protein to P.abysii glycogen synthase, [5-(2-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]{(2S)-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]pyrrolidin-1-yl}methanone, OLEIC ACID (3 entities in total)
• Functional Keywords: orexin, suvorexant, sb-674042, membrane protein-transferase complex, signaling protein
• Biological source: Homo sapiens (Human); More
• Cellular location: Cell membrane; Multi-pass membrane protein: O43613
• Total number of polymer chains: 1
• Total formula weight: 63698.47

Authors

Yin, J.,Brautigam, C.A.,Shao, Z.,Clark, L.,Harrell, C.M.,Gotter, A.L.,Coleman, P.J.,Renger, J.J.,Rosenbaum, D.M. (deposition date: 2015-04-29, release date: 2016-03-09, Last modification date: 2024-10-16)

Primary citation

Yin, J.,Babaoglu, K.,Brautigam, C.A.,Clark, L.,Shao, Z.,Scheuermann, T.H.,Harrell, C.M.,Gotter, A.L.,Roecker, A.J.,Winrow, C.J.,Renger, J.J.,Coleman, P.J.,Rosenbaum, D.M.
Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors.
Nat.Struct.Mol.Biol., 23:293-299, 2016

PubMed Abstract: The orexin (also known as hypocretin) G protein-coupled receptors (GPCRs) regulate sleep and other behavioral functions in mammals, and are therapeutic targets for sleep and wake disorders. The human receptors hOX1R and hOX2R, which are 64% identical in sequence, have overlapping but distinct physiological functions and potential therapeutic profiles. We determined structures of hOX1R bound to the OX1R-selective antagonist SB-674042 and the dual antagonist suvorexant at 2.8-Å and 2.75-Å resolution, respectively, and used molecular modeling to illuminate mechanisms of antagonist subtype selectivity between hOX1R and hOX2R. The hOX1R structures also reveal a conserved amphipathic α-helix, in the extracellular N-terminal region, that interacts with orexin-A and is essential for high-potency neuropeptide activation at both receptors. The orexin-receptor crystal structures are valuable tools for the design and development of selective orexin-receptor antagonists and agonists.

PubMed: 26950369
DOI: 10.1038/nsmb.3183

Experimental method

X-RAY DIFFRACTION (2.832 Å)