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Yorodumi- PDB-7fee: Crystal structure of the allosteric modulator ZCZ011 binding to C... -
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-Basic information
Entry | Database: PDB / ID: 7fee | ||||||
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Title | Crystal structure of the allosteric modulator ZCZ011 binding to CP55940-bound cannabinoid receptor 1 | ||||||
Components | Cannabinoid receptor 1,GlgA glycogen synthase | ||||||
Keywords | MEMBRANE 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 / alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) 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 / alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity / negative regulation of fatty acid beta-oxidation / negative regulation of dopamine secretion / positive regulation of acute inflammatory response to antigenic stimulus / negative regulation of serotonin secretion / regulation of feeding behavior / regulation of presynaptic cytosolic calcium ion concentration / negative regulation of action potential / Class A/1 (Rhodopsin-like receptors) / positive regulation of blood pressure / positive regulation of fever generation / regulation of metabolic process / axonal fasciculation / glycogen biosynthetic process / 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 / response to nutrient / regulation of synaptic transmission, glutamatergic / negative regulation of blood pressure / 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 / glucose homeostasis / actin cytoskeleton / 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 / glutamatergic synapse / identical protein binding / plasma membrane / cytoplasm / cytosol Similarity search - Function | ||||||
Biological species | Homo sapiens (human) Pyrococcus abyssi GE5 (archaea) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å | ||||||
Authors | Wang, X. / Zhao, C. / Shao, Z. | ||||||
Funding support | 1items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7fee.cif.gz | 224.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7fee.ent.gz | 178.2 KB | Display | PDB format |
PDBx/mmJSON format | 7fee.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/fe/7fee ftp://data.pdbj.org/pub/pdb/validation_reports/fe/7fee | HTTPS FTP |
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-Related structure data
Related structure data | 7wv9C 5u09S S: Starting model for refinement C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
-Protein , 1 types, 1 molecules A
#1: Protein | 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 | #3: Chemical | ChemComp-9GF / | #4: Chemical | ChemComp-7IC / | #5: Chemical | #6: Chemical | ChemComp-GOL / #7: Chemical | #8: Chemical | ChemComp-OLA / #9: Water | ChemComp-HOH / | |
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-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.72 Å3/Da / Density % sol: 54.78 % |
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Crystal grow | Temperature: 293 K / Method: lipidic cubic phase / pH: 6 Details: 25-36% PEG 300, 100Mm MES pH 6.0, 120-190mM Magnesium Sulfate |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: SYNCHROTRON / Site: SPring-8 / Beamline: BL32XU / Wavelength: 1 Å |
Detector | Type: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 20, 2020 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1 Å / Relative weight: 1 |
Reflection | Resolution: 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 shell | Resolution: 2.7→2.79 Å / Num. unique obs: 1694 / CC1/2: 0.733 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 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
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Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso max: 192.18 Å2 / Biso mean: 107.2729 Å2 / Biso min: 61.05 Å2 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: final / Resolution: 2.7→42.6 Å
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LS refinement shell | Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 11
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Refinement TLS params. | Method: refined / Origin x: 9.5811 Å / Origin y: 14.486 Å / Origin z: 18.5805 Å
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Refinement TLS group |
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