PDBsum entry 6tot

Membrane protein

PDB id: 6tot

Contents

Protein chains

300 a.a.

303 a.a.

Ligands

NRK ×2

PG4

SO4 ×4

SOG ×9

PGW ×2

Waters ×43

PDB id:

6tot

Name:

Membrane protein

Title:

Crystal structure of the orexin-1 receptor in complex with lemborexant

Structure:

Orexin receptor type 1. Chain: a, b. Synonym: ox1r,hypocretin receptor type 1. Engineered: yes. Mutation: yes. Other_details: lemborexant bound in the orthosteric site

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: hcrtr1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

2.22Å R-factor: 0.207 R-free: 0.239

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:

11-Dec-19 Release date: 15-Jan-20

Protein chain

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

Seq: 425 a.a.

Struc: 300 a.a.*

Protein chain

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

Seq: 425 a.a.

Struc: 303 a.a.*

* PDB and UniProt seqs differ at 22 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.