PDBsum entry 4zjc

Signaling protein

PDB id: 4zjc

Contents

Protein chain

503 a.a.

Ligands

4OT

OLA ×2

PDB id:

4zjc

Name:

Signaling protein

Title:

Structures of the human ox1 orexin receptor bound to selective and dual antagonists

Structure:

Human ox1r fusion protein to p.Abysii glycogen synthase. Chain: a. Fragment: unp o43613 residues 1-245,unp q9v2j8 residues 218-413,unp o43613 residues 288-380. Engineered: yes

Source:

Homo sapiens, pyrococcus abyssi (strain ge5 / orsay). Human. Organism_taxid: 9606, 272844. Strain: ge5 / orsay. Gene: hcrtr1, pab2292, pyrab00770. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

2.83Å R-factor: 0.219 R-free: 0.262

Authors:

J.Yin,C.A.Brautigam,Z.Shao,L.Clark,C.M.Harrell,A.L.Gotter, P.J.Coleman,J.J.Renger,D.M.Rosenbaum

Key ref:

J.Yin et al. (2016). Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors. Nat Struct Biol, 23, 293-299. PubMed id: 26950369 DOI: 10.1038/nsmb.3183

Date:

29-Apr-15 Release date: 09-Mar-16

Protein chain

O43613  (OX1R_HUMAN) -  Orexin/Hypocretin receptor type 1 from Homo sapiens

Seq: 425 a.a.

Struc: 503 a.a.*

Protein chain

Q9V2J8  (Q9V2J8_PYRAB) -  Glycogen synthase from Pyrococcus abyssi (strain GE5 / Orsay)

Seq: 437 a.a.

Struc: 503 a.a.*

* PDB and UniProt seqs differ at 401 residue positions (black crosses)

DOI no: 10.1038/nsmb.3183

Nat Struct Biol 23:293-299 (2016)

PubMed id: 26950369

Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors.

J.Yin, K.Babaoglu, C.A.Brautigam, L.Clark, Z.Shao, T.H.Scheuermann, C.M.Harrell, A.L.Gotter, A.J.Roecker, C.J.Winrow, J.J.Renger, P.J.Coleman, D.M.Rosenbaum.

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.