PDBsum entry 5ws3

Signaling protein

PDB id: 5ws3

Contents

Protein chain

506 a.a.

Ligands

7MA

OLA ×4

1PE ×2

Waters ×12

PDB id:

5ws3

Name:

Signaling protein

Title:

Crystal structures of human orexin 2 receptor bound to the selective antagonist empa determined by serial femtosecond crystallography at sacla

Structure:

Orexin receptor type 2,glga glycogen synthase,orexin receptor type 2. Chain: a. Fragment: unp residues 3-254,unp residues 218-413,unp residues 294- 388. Synonym: ox2r,hypocretin receptor type 2,glycogen synthase. Engineered: yes. Other_details: chimera protein of unp residues 3-254 from orexin receptor type 2 (o43614), unp residues 218-413 from glga glycogen

Source:

Homo sapiens, pyrococcus abyssi (strain ge5 / orsay). Human. Organism_taxid: 9606, 272844. Strain: ge5 / orsay. Gene: hcrtr2, pab2292. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

2.30Å R-factor: 0.200 R-free: 0.219

Authors:

R.Suno,K.Kimura,T.Nakane,K.Yamashita,J.Wang,T.Fujiwara,Y.Yamanaka, D.Im,H.Tsujimoto,M.Sasanuma,S.Horita,T.Hirokawa,E.Nango,K.Tono, T.Kameshima,T.Hatsui,Y.Joti,M.Yabashi,K.Shimamoto,M.Yamamoto, D.M.Rosenbaum,S.Iwata,T.Shimamura,T.Kobayashi

Key ref:

R.Suno et al. (2018). Crystal Structures of Human Orexin 2 Receptor Bound to the Subtype-Selective Antagonist EMPA. Structure, 26, 7. PubMed id: 29225076 DOI: 10.1016/j.str.2017.11.005

Date:

05-Dec-16 Release date: 13-Dec-17

Protein chain

O43614  (OX2R_HUMAN) -  Orexin receptor type 2 from Homo sapiens

Seq: 444 a.a.

Struc: 506 a.a.*

Protein chain

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

Seq: 437 a.a.

Struc: 506 a.a.*

* PDB and UniProt seqs differ at 411 residue positions (black crosses)

DOI no: 10.1016/j.str.2017.11.005

Structure 26:7 (2018)

PubMed id: 29225076

Crystal Structures of Human Orexin 2 Receptor Bound to the Subtype-Selective Antagonist EMPA.

R.Suno, K.T.Kimura, T.Nakane, K.Yamashita, J.Wang, T.Fujiwara, Y.Yamanaka, D.Im, S.Horita, H.Tsujimoto, M.S.Tawaramoto, T.Hirokawa, E.Nango, K.Tono, T.Kameshima, T.Hatsui, Y.Joti, M.Yabashi, K.Shimamoto, M.Yamamoto, D.M.Rosenbaum, S.Iwata, T.Shimamura, T.Kobayashi.

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 OX₂R structures in complex with selective antagonists and previously determined OX₁R/OX₂R structures bound to non-selective antagonists revealed that the residue at positions 2.61 and 3.33 were critical for the antagonist selectivity in OX₂R. The importance of these residues for binding selectivity to OX₂R was also revealed by molecular dynamics simulation. These results should facilitate the development of antagonists for orexin receptors.