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- PDB-7fee: Crystal structure of the allosteric modulator ZCZ011 binding to C... -

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Basic information

Entry
Database: PDB / ID: 7fee
TitleCrystal structure of the allosteric modulator ZCZ011 binding to CP55940-bound cannabinoid receptor 1
ComponentsCannabinoid receptor 1,GlgA glycogen synthase
KeywordsMEMBRANE PROTEIN / signal protein / GPCR
Function / homology
Function and homology information


cannabinoid signaling pathway / regulation of penile erection / retrograde trans-synaptic signaling by endocannabinoid / cannabinoid receptor activity / negative regulation of mast cell activation / trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / glycogen (starch) synthase activity / negative regulation of fatty acid beta-oxidation / negative regulation of dopamine secretion / positive regulation of acute inflammatory response to antigenic stimulus ...cannabinoid signaling pathway / regulation of penile erection / retrograde trans-synaptic signaling by endocannabinoid / cannabinoid receptor activity / negative regulation of mast cell activation / trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / glycogen (starch) synthase activity / negative regulation of fatty acid beta-oxidation / negative regulation of dopamine secretion / positive regulation of acute inflammatory response to antigenic stimulus / regulation of feeding behavior / negative regulation of serotonin secretion / regulation of presynaptic cytosolic calcium ion concentration / negative regulation of action potential / Class A/1 (Rhodopsin-like receptors) / positive regulation of blood pressure / regulation of metabolic process / positive regulation of fever generation / axonal fasciculation / regulation of synaptic transmission, GABAergic / regulation of insulin secretion / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / GABA-ergic synapse / maternal process involved in female pregnancy / regulation of synaptic transmission, glutamatergic / negative regulation of blood pressure / response to nutrient / response to cocaine / G protein-coupled receptor activity / response to nicotine / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / memory / positive regulation of neuron projection development / actin cytoskeleton / glucose homeostasis / presynaptic membrane / G alpha (i) signalling events / growth cone / spermatogenesis / response to ethanol / mitochondrial outer membrane / response to lipopolysaccharide / membrane raft / positive regulation of apoptotic process / nucleotide binding / glutamatergic synapse / identical protein binding / plasma membrane / cytoplasm
Similarity search - Function
Cannabinoid receptor type 1 / Glycosyl transferases group 1 / Cannabinoid receptor family / Bacterial/plant glycogen synthase / Starch synthase, catalytic domain / Starch synthase catalytic domain / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM ...Cannabinoid receptor type 1 / Glycosyl transferases group 1 / Cannabinoid receptor family / Bacterial/plant glycogen synthase / Starch synthase, catalytic domain / Starch synthase catalytic domain / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family)
Similarity search - Domain/homology
Chem-7IC / Chem-9GF / CHOLESTEROL / OLEIC ACID / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / DI(HYDROXYETHYL)ETHER / Cannabinoid receptor 1 / Glycogen synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
Pyrococcus abyssi GE5 (archaea)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsWang, X. / Zhao, C. / Shao, Z.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Chem Biol / Year: 2022
Title: Molecular mechanism of allosteric modulation for the cannabinoid receptor CB1.
Authors: Xin Yang / Xuehui Wang / Zheng Xu / Chao Wu / Yangli Zhou / Yifei Wang / Guifeng Lin / Kan Li / Ming Wu / Anjie Xia / Jingming Liu / Lin Cheng / Jun Zou / Wei Yan / Zhenhua Shao / Shengyong Yang /
Abstract: Given the promising clinical value of allosteric modulators of G protein-coupled-receptors (GPCRs), mechanistic understanding of how these modulators alter GPCR function is of significance. Here, we ...Given the promising clinical value of allosteric modulators of G protein-coupled-receptors (GPCRs), mechanistic understanding of how these modulators alter GPCR function is of significance. Here, we report the crystallographic and cryo-electron microscopy structures of the cannabinoid receptor CB1 bound to the positive allosteric modulator (PAM) ZCZ011. These structures show that ZCZ011 binds to an extrahelical site in the transmembrane 2 (TM2)-TM3-TM4 surface. Through (un)biased molecular dynamics simulations and mutagenesis experiments, we show that TM2 rearrangement is critical for the propagation of allosteric signals. ZCZ011 exerts a PAM effect by promoting TM2 rearrangement in favor of receptor activation and increasing the population of receptors that adopt an active conformation. In contrast, ORG27569, a negative allosteric modulator (NAM) of CB1, also binds to the TM2-TM3-TM4 surface and exerts a NAM effect by impeding the TM2 rearrangement. Our findings fill a gap in the understanding of CB1 allosteric regulation and could guide the rational design of CB1 allosteric modulators.
History
DepositionJul 19, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 15, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 10, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Apr 3, 2024Group: Structure summary / Category: struct / Item: _struct.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Cannabinoid receptor 1,GlgA glycogen synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,50017
Polymers63,5641
Non-polymers3,93616
Water32418
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)43.790, 74.330, 184.200
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Cannabinoid receptor 1,GlgA glycogen synthase / CB-R / CB1 / CANN6 / Glycogen synthase


Mass: 63564.348 Da / Num. of mol.: 1 / Mutation: S203K,T210A,E273K,T283V,R340E,N393D
Source method: isolated from a genetically manipulated source
Details: Cannabinoid receptor 1 inserted with GlgA glycogen synthase
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Pyrococcus abyssi GE5 (archaea)
Gene: CNR1, CNR, PAB2292 / Plasmid: PFASTbac / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P21554, UniProt: Q9V2J8

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Non-polymers , 8 types, 34 molecules

#2: Chemical ChemComp-CLR / CHOLESTEROL / Cholesterol


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O
#3: Chemical ChemComp-9GF / 2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol / CP 55,940


Mass: 376.573 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H40O3
#4: Chemical ChemComp-7IC / 6-methyl-3-[(1S)-2-nitro-1-thiophen-2-yl-ethyl]-2-phenyl-1H-indole


Mass: 362.445 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H18N2O2S
#5: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#7: Chemical ChemComp-OLC / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / 1-Oleoyl-R-glycerol


Mass: 356.540 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H40O4
#8: Chemical
ChemComp-OLA / OLEIC ACID / Oleic acid


Mass: 282.461 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: C18H34O2
#9: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 18 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.72 Å3/Da / Density % sol: 54.78 %
Crystal growTemperature: 293 K / Method: lipidic cubic phase / pH: 6
Details: 25-36% PEG 300, 100Mm MES pH 6.0, 120-190mM Magnesium Sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL32XU / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 20, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→42.6 Å / Num. obs: 17318 / Redundancy: 32.7 % / Biso Wilson estimate: 86.93 Å2 / CC1/2: 0.987 / Net I/σ(I): 12.6
Reflection shellResolution: 2.7→2.79 Å / Num. unique obs: 1694 / CC1/2: 0.733

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSdata scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5u09

5u09


Resolution: 2.7→42.6 Å / SU ML: 0.52 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 38.83 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.319 1597 9.27 %
Rwork0.2928 15637 -
obs0.2953 17234 99.75 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 192.18 Å2 / Biso mean: 107.2729 Å2 / Biso min: 61.05 Å2
Refinement stepCycle: final / Resolution: 2.7→42.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3815 0 0 18 3833
Biso mean---119.87 -
Num. residues----502
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.7-2.790.49481430.46681398154199
2.79-2.890.3991410.438913811522100
2.89-30.49841400.411413731513100
3-3.140.41911430.367614071550100
3.14-3.30.36921440.349513981542100
3.3-3.510.36971420.341514021544100
3.51-3.780.35571450.335314201565100
3.78-4.160.29981450.284614231568100
4.16-4.760.29831470.262814351582100
4.76-60.29481480.287514491597100
6-42.60.2821590.245415511710100
Refinement TLS params.Method: refined / Origin x: 9.5811 Å / Origin y: 14.486 Å / Origin z: 18.5805 Å
111213212223313233
T0.6793 Å20.1093 Å20.0066 Å2-0.5885 Å20.0229 Å2--0.7068 Å2
L2.8017 °2-0.1493 °21.5675 °2-1.094 °2-0.2173 °2--3.5103 °2
S0.0487 Å °-0.6682 Å °-0.2358 Å °0.3296 Å °0.1335 Å °-0.24 Å °0.2689 Å °0.1431 Å °-0.1589 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA97 - 1196
2X-RAY DIFFRACTION1allB1 - 2
3X-RAY DIFFRACTION1allC1
4X-RAY DIFFRACTION1allD1
5X-RAY DIFFRACTION1allE2 - 3
6X-RAY DIFFRACTION1allF2 - 6
7X-RAY DIFFRACTION1allG1 - 2
8X-RAY DIFFRACTION1allH1 - 44
9X-RAY DIFFRACTION1allI1 - 4

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