6TP6

Crystal structure of the Orexin-1 receptor in complex with filorexant

PDB DOI: https://doi.org/10.2210/pdb6TP6/pdb

Classification: MEMBRANE PROTEIN
Organism(s): Homo sapiens
Expression System: Spodoptera frugiperda
Mutation(s): Yes
Membrane Protein: Yes OPMPDBTMMemProtMDmpstruc

Deposited: 2019-12-12 Released: 2020-01-01
Deposition Author(s): Rappas, M., Ali, A., Bennett, K.A., Brown, J.D., Bucknell, S.J., Congreve, M., Cooke, R.M., Cseke, G., de Graaf, C., Dore, A.S., Errey, J.C., Jazayeri, A., Marshall, F.H., Mason, J.S., Mould, R., Patel, J.C., Tehan, B.G., Weir, M., Christopher, J.A.
Funding Organization(s): National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.34 Å
R-Value Free: 0.244
R-Value Work: 0.211
R-Value Observed: 0.213

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.5 of the entry. See complete history.

Literature

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

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

(2020) J Med Chem 63: 1528-1543

PubMed: 31860301 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acs.jmedchem.9b01787
Primary Citation of Related Structures:
6TO7, 6TOD, 6TOS, 6TOT, 6TP3, 6TP4, 6TP6, 6TPG, 6TPJ, 6TPN, 6TQ4, 6TQ6, 6TQ7, 6TQ9

PubMed Abstract:
The orexin system, which consists of the two G protein-coupled receptors OX ₁ and OX ₂, 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 OX ₁ and OX ₂ can be achieved are discussed.

Organizational Affiliation

Sosei Heptares , Steinmetz Building, Granta Park , Cambridge CB21 6DG , U.K.

Macromolecule Content

Total Structure Weight: 89.37 kDa
Atom Count: 5,251
Modelled Residue Count: 608
Deposited Residue Count: 736
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Orexin receptor type 1	A, B	368	Homo sapiens	Mutation(s): 11 Gene Names: HCRTR1 Membrane Entity: Yes
UniProt & NIH Common Fund Data Resources
Find proteins for O43613 (Homo sapiens) Explore O43613 Go to UniProtKB: O43613
PHAROS: O43613 GTEx: ENSG00000121764
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	O43613
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 6 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
PGW Query on PGW Download Ideal Coordinates CCD File SDF format, chain M [auth A] SDF format, chain V [auth B] MOL2 format, chain M [auth A] MOL2 format, chain V [auth B] mmCIF format, chain M [auth A] mmCIF format, chain V [auth B]	M [auth A], V [auth B]	(1R)-2-{[(S)-{[(2S)-2,3-dihydroxypropyl]oxy}(hydroxy)phosphoryl]oxy}-1-[(hexadecanoyloxy)methyl]ethyl (9Z)-octadec-9-enoate C₄₀ H₇₇ O₁₀ P PAZGBAOHGQRCBP-HGWHEPCSSA-N		Interactions Focus chain M [auth A] Focus chain V [auth B] Interactions & Density Focus chain M [auth A] Focus chain V [auth B]
NT5 (Subject of Investigation/LOI) Query on NT5 Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain N [auth B] MOL2 format, chain C [auth A] MOL2 format, chain N [auth B] mmCIF format, chain C [auth A] mmCIF format, chain N [auth B]	C [auth A], N [auth B]	[(2~{R},5~{R})-5-[(5-fluoranylpyridin-2-yl)oxymethyl]-2-methyl-piperidin-1-yl]-(5-methyl-2-pyrimidin-2-yl-phenyl)methanone C₂₄ H₂₅ F N₄ O₂ NPFDWHQSDBWQLH-QZTJIDSGSA-N		Interactions Focus chain C [auth A] Focus chain N [auth B] Interactions & Density Focus chain C [auth A] Focus chain N [auth B]
SOG Query on SOG Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain K [auth A] SDF format, chain R [auth B] SDF format, chain S [auth B] SDF format, chain T [auth B] SDF format, chain U [auth B] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain K [auth A] MOL2 format, chain R [auth B] MOL2 format, chain S [auth B] MOL2 format, chain T [auth B] MOL2 format, chain U [auth B] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain K [auth A] mmCIF format, chain R [auth B] mmCIF format, chain S [auth B] mmCIF format, chain T [auth B] mmCIF format, chain U [auth B]	G [auth A] H [auth A] I [auth A] J [auth A] K [auth A] G [auth A], H [auth A], I [auth A], J [auth A], K [auth A], R [auth B], S [auth B], T [auth B], U [auth B]	octyl 1-thio-beta-D-glucopyranoside C₁₄ H₂₈ O₅ S CGVLVOOFCGWBCS-RGDJUOJXSA-N		Interactions Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain R [auth B] Focus chain S [auth B] Focus chain T [auth B] Focus chain U [auth B] Interactions & Density Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain R [auth B] Focus chain S [auth B] Focus chain T [auth B] Focus chain U [auth B]
PG4 Query on PG4 Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain O [auth B] MOL2 format, chain D [auth A] MOL2 format, chain O [auth B] mmCIF format, chain D [auth A] mmCIF format, chain O [auth B]	D [auth A], O [auth B]	TETRAETHYLENE GLYCOL C₈ H₁₈ O₅ UWHCKJMYHZGTIT-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain O [auth B] Interactions & Density Focus chain D [auth A] Focus chain O [auth B]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain P [auth B] SDF format, chain Q [auth B] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain P [auth B] MOL2 format, chain Q [auth B] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain P [auth B] mmCIF format, chain Q [auth B]	E [auth A], F [auth A], P [auth B], Q [auth B]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain E [auth A] Focus chain F [auth A] Focus chain P [auth B] Focus chain Q [auth B] Interactions & Density Focus chain E [auth A] Focus chain F [auth A] Focus chain P [auth B] Focus chain Q [auth B]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain L [auth A] MOL2 format, chain L [auth A] mmCIF format, chain L [auth A]	L [auth A]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain L [auth A] Interactions & Density Focus chain L [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
NT5	BindingDB: 6TP6	Ki: min: 0.63, max: 2.9 (nM) from 5 assay(s)
NT5	BindingDB: 6TP6	IC50: min: 11, max: 16 (nM) from 2 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.34 Å
R-Value Free: 0.244
R-Value Work: 0.211
R-Value Observed: 0.213
Space Group: P 1 2₁ 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 59.892	α = 90
b = 146.202	β = 111.12
c = 72.328	γ = 90

Software Package:

Software Name	Purpose
PHENIX	refinement
PDB_EXTRACT	data extraction
XDS	data reduction
STARANISO	data scaling
PHASER	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History & Funding Information

Deposition Data

Released Date: 2020-01-01

Deposition Author(s):

Funding Organization	Location	Grant Number
National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA)	United States	R01DA039553

Revision History (Full details and data files)

Version 1.0: 2020-01-01
Type: Initial release
Version 1.1: 2020-01-29
Changes: Database references
Version 1.2: 2020-03-11
Changes: Database references
Version 1.3: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Derived calculations, Structure summary
Version 1.4: 2024-01-24
Changes: Data collection, Database references, Refinement description, Structure summary
Version 1.5: 2024-11-20
Changes: Structure summary

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Help and Resources

6TP6

Crystal structure of the Orexin-1 receptor in complex with filorexant

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

Entity ID: 1

UniProt & NIH Common Fund Data Resources

Entity Groups

Sequence Annotations

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Experimental Data

Structure Validation

Ligand Structure Quality Assessment

Deposition Data

Revision History (Full details and data files)