6DK1

Human sigma-1 receptor bound to (+)-pentazocine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.12 Å
  • R-Value Free: 0.278 
  • R-Value Work: 0.247 
  • R-Value Observed: 0.248 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structural basis for sigma1receptor ligand recognition.

Schmidt, H.R.Betz, R.M.Dror, R.O.Kruse, A.C.

(2018) Nat Struct Mol Biol 25: 981-987

  • DOI: https://doi.org/10.1038/s41594-018-0137-2
  • Primary Citation of Related Structures:  
    6DJZ, 6DK0, 6DK1

  • PubMed Abstract: 

    The σ 1 receptor is a poorly understood membrane protein expressed throughout the human body. Ligands targeting the σ 1 receptor are in clinical trials for treatment of Alzheimer's disease, ischemic stroke, and neuropathic pain. However, relatively little is known regarding the σ 1 receptor's molecular function. Here, we present crystal structures of human σ 1 receptor bound to the antagonists haloperidol and NE-100, and the agonist (+)-pentazocine, at crystallographic resolutions of 3.1 Å, 2.9 Å, and 3.1 Å, respectively. These structures reveal a unique binding pose for the agonist. The structures and accompanying molecular dynamics (MD) simulations identify agonist-induced structural rearrangements in the receptor. Additionally, we show that ligand binding to σ 1 is a multistep process that is rate limited by receptor conformational change. We used MD simulations to reconstruct a ligand binding pathway involving two major conformational changes. These data provide a framework for understanding the molecular basis for σ 1 agonism.


  • Organizational Affiliation

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Sigma non-opioid intracellular receptor 1
A, B, C
227Homo sapiensMutation(s): 0 
Gene Names: SIGMAR1OPRS1SRBPAAG8
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for Q99720 (Homo sapiens)
Explore Q99720 
Go to UniProtKB:  Q99720
PHAROS:  Q99720
GTEx:  ENSG00000147955 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ99720
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
OLC
Query on OLC

Download Ideal Coordinates CCD File 
DA [auth C]
EA [auth C]
FA [auth C]
GA [auth C]
HA [auth C]
DA [auth C],
EA [auth C],
FA [auth C],
GA [auth C],
HA [auth C],
IA [auth C],
M [auth A],
N [auth A],
U [auth B],
V [auth B],
W [auth B]
(2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate
C21 H40 O4
RZRNAYUHWVFMIP-GDCKJWNLSA-N
GM4
Query on GM4

Download Ideal Coordinates CCD File 
D [auth A],
O [auth B],
X [auth C]
(2S,6S,11S)-6,11-dimethyl-3-(3-methylbut-2-en-1-yl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-8-ol
C19 H27 N O
VOKSWYLNZZRQPF-CCKFTAQKSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
AA [auth C]
E [auth A]
F [auth A]
G [auth A]
H [auth A]
AA [auth C],
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
K [auth A],
P [auth B],
Q [auth B],
R [auth B],
S [auth B],
Y [auth C],
Z [auth C]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
BA [auth C],
CA [auth C],
L [auth A],
T [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.12 Å
  • R-Value Free: 0.278 
  • R-Value Work: 0.247 
  • R-Value Observed: 0.248 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 84.837α = 90
b = 128.59β = 90
c = 109.18γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Science Foundation (NSF, United States)United StatesDGE1745303
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesR01 GM119185

Revision History  (Full details and data files)

  • Version 1.0: 2018-10-17
    Type: Initial release
  • Version 1.1: 2019-11-27
    Changes: Author supporting evidence
  • Version 1.2: 2023-10-11
    Changes: Data collection, Database references, Refinement description