PDBsum entry 6tpj

Membrane protein

PDB id: 6tpj

Contents

Protein chains

499 a.a.

Ligands

OLA ×34

SUV ×2

NH4 ×5

PG4 ×2

Waters ×226

PDB id:

6tpj

Name:

Membrane protein

Title:

Crystal structure of the orexin-2 receptor in complex with suvorexant at 2.76 a resolution

Structure:

Orexin receptor type 2,glga glycogen synthase,hypocretin receptor-2. Chain: a, b. Synonym: ox2r,hypocretin receptor type 2,glycogen synthase,cdna, flj95033,homo sapiens hypocretin (orexin) receptor 2 (hcrtr2),mRNA. Engineered: yes. Mutation: yes

Source:

Homo sapiens, pyrococcus abyssi ge5. Human. Organism_taxid: 9606, 272844. Gene: hcrtr2, pab2292. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

2.74Å R-factor: 0.209 R-free: 0.254

Authors:

M.Rappas,A.Ali,K.A.Bennett,J.D.Brown,S.J.Bucknell,M.Congreve, R.M.Cooke,G.Cseke,C.De Graaf,A.S.Dore,J.C.Errey,A.Jazayeri, F.H.Marshall,J.S.Mason,R.Mould,J.C.Patel,B.G.Tehan,M.Weir, J.A.Christopher

Key ref:

M.Rappas et al. (2020). Comparison of Orexin 1 and Orexin 2 Ligand Binding Modes Using X-ray Crystallography and Computational Analysis. J Med Chem, 63, 1528-1543. PubMed id: 31860301 DOI: 10.1021/acs.jmedchem.9b01787

Date:

13-Dec-19 Release date: 01-Jan-20

Protein chains

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

Seq: 444 a.a.

Struc: 499 a.a.*

Protein chains

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

Seq: 437 a.a.

Struc: 499 a.a.*

* PDB and UniProt seqs differ at 422 residue positions (black crosses)

DOI no: 10.1021/acs.jmedchem.9b01787

J Med Chem 63:1528-1543 (2020)

PubMed id: 31860301

Comparison of Orexin 1 and Orexin 2 Ligand Binding Modes Using X-ray Crystallography and Computational Analysis.

M.Rappas, A.A.E.Ali, K.A.Bennett, J.D.Brown, S.J.Bucknell, M.Congreve, R.M.Cooke, G.Cseke, C.de Graaf, A.S.Doré, J.C.Errey, A.Jazayeri, F.H.Marshall, J.S.Mason, R.Mould, J.C.Patel, B.G.Tehan, M.Weir, J.A.Christopher.

ABSTRACT

The orexin system, which consists of the two G protein-coupled receptors OX₁ and OX₂, activated by the neuropeptides OX-A and OX-B, is firmly established as a key regulator of behavioral arousal, sleep, and wakefulness and has been an area of intense research effort over the past two decades. X-ray structures of the receptors in complex with 10 new antagonist ligands from diverse chemotypes are presented, which complement the existing structural information for the system and highlight the critical importance of lipophilic hotspots and water molecules for these peptidergic GPCR targets. Learnings from the structural information regarding the utility of pharmacophore models and how selectivity between OX₁ and OX₂ can be achieved are discussed.