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- PDB-9cib: CryoEM Structure of HCA2 DREADD Gi1 in complex with FCH-2296413 (... -

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Entry
Database: PDB / ID: 9cib
TitleCryoEM Structure of HCA2 DREADD Gi1 in complex with FCH-2296413 (Local Refinement)
ComponentsHydroxycarboxylic acid receptor 2
KeywordsMEMBRANE PROTEIN / GPCR / HCA2 / DREADD
Function / homology
Function and homology information


Hydroxycarboxylic acid-binding receptors / Class A/1 (Rhodopsin-like receptors) / nicotinic acid receptor activity / positive regulation of neutrophil apoptotic process / purinergic nucleotide receptor activity / G alpha (i) signalling events / positive regulation of adiponectin secretion / negative regulation of lipid catabolic process / G protein-coupled receptor activity / G protein-coupled receptor signaling pathway ...Hydroxycarboxylic acid-binding receptors / Class A/1 (Rhodopsin-like receptors) / nicotinic acid receptor activity / positive regulation of neutrophil apoptotic process / purinergic nucleotide receptor activity / G alpha (i) signalling events / positive regulation of adiponectin secretion / negative regulation of lipid catabolic process / G protein-coupled receptor activity / G protein-coupled receptor signaling pathway / apoptotic process / GTP binding / membrane / plasma membrane
Similarity search - Function
: / 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
: / Hydroxycarboxylic acid receptor 2
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.62 Å
AuthorsKrumm, B.E. / Kang, H.J. / Diberto, J.F. / Kapolka, N.J. / Gumpper, R.H. / Olsen, R.H.J. / Huang, X.P. / Zhang, S. / Fay, J.F. / Roth, B.L.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)5R01MH112205 United States
CitationJournal: Cell / Year: 2024
Title: Structure-guided design of a peripherally restricted chemogenetic system.
Authors: Hye Jin Kang / Brian E Krumm / Adrien Tassou / Matan Geron / Jeffrey F DiBerto / Nicholas J Kapolka / Ryan H Gumpper / Kensuke Sakamoto / D Dewran Kocak / Reid H J Olsen / Xi-Ping Huang / ...Authors: Hye Jin Kang / Brian E Krumm / Adrien Tassou / Matan Geron / Jeffrey F DiBerto / Nicholas J Kapolka / Ryan H Gumpper / Kensuke Sakamoto / D Dewran Kocak / Reid H J Olsen / Xi-Ping Huang / Shicheng Zhang / Karen L Huang / Saheem A Zaidi / MyV T Nguyen / Min Jeong Jo / Vsevolod Katritch / Jonathan F Fay / Grégory Scherrer / Bryan L Roth /
Abstract: Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools for remotely controlling cellular signaling, neural activity, behavior, and physiology. Using a structure- ...Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools for remotely controlling cellular signaling, neural activity, behavior, and physiology. Using a structure-guided approach, we provide a peripherally restricted Gi-DREADD, hydroxycarboxylic acid receptor DREADD (HCAD), whose native receptor is minimally expressed in the brain, and a chemical actuator that does not cross the blood-brain barrier (BBB). This was accomplished by combined mutagenesis, analoging via an ultra-large make-on-demand library, structural determination of the designed DREADD receptor via cryoelectron microscopy (cryo-EM), and validation of HCAD function. Expression and activation of HCAD in dorsal root ganglion (DRG) neurons inhibit action potential (AP) firing and reduce both acute and tissue-injury-induced inflammatory pain. The HCAD chemogenetic system expands the possibilities for studying numerous peripheral systems with little adverse effects on the central nervous system (CNS). The structure-guided approach used to generate HCAD also has the potential to accelerate the development of emerging chemogenetic tools for basic and translational sciences.
History
DepositionJul 3, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 14, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
R: Hydroxycarboxylic acid receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4362
Polymers34,2481
Non-polymers1881
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Hydroxycarboxylic acid receptor 2 / G-protein coupled receptor 109 / G-protein coupled receptor 109A / G-protein coupled receptor HM74 ...G-protein coupled receptor 109 / G-protein coupled receptor 109A / G-protein coupled receptor HM74 / Niacin receptor 1 / Nicotinic acid receptor / Protein PUMA-G


Mass: 34247.727 Da / Num. of mol.: 1 / Mutation: R108K,D120A
Source method: isolated from a genetically manipulated source
Details: Protein starts at M1, GTT sequence from protease cleavage site, Mutation D120A, Mutation R108K to convert WT to DREADD.
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Hcar2, Gpr109, Gpr109a, Gpr109b, Niacr1, Pumag / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9EP66
#2: Chemical ChemComp-XI9 / (3M,4aR,5aR)-3-(1H-tetrazol-5-yl)-4,4a,5,5a-tetrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazole


Mass: 188.189 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H8N6 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Mouse HCAD-Gai1 in complex with FCH-2296413 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenConc.: 3.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1600 nm / Nominal defocus min: 1300 nm
Image recordingElectron dose: 47 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.62 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 250000 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT

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