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- PDB-4mqt: Structure of active human M2 muscarinic acetylcholine receptor bo... -

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Basic information

Entry
Database: PDB / ID: 4mqt
TitleStructure of active human M2 muscarinic acetylcholine receptor bound to the agonist iperoxo and allosteric modulator LY2119620
Components
  • Muscarinic acetylcholine receptor M2
  • Nanobody 9-8
KeywordsSIGNALING PROTEIN / G protein-coupled receptor / Muscarinic acetylcholine receptor / allosteric modulation
Function / homology
Function and homology information


phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway / Muscarinic acetylcholine receptors / G protein-coupled acetylcholine receptor activity / cholinergic synapse / regulation of smooth muscle contraction / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / arrestin family protein binding / regulation of heart contraction / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / presynaptic modulation of chemical synaptic transmission ...phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway / Muscarinic acetylcholine receptors / G protein-coupled acetylcholine receptor activity / cholinergic synapse / regulation of smooth muscle contraction / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / arrestin family protein binding / regulation of heart contraction / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / presynaptic modulation of chemical synaptic transmission / clathrin-coated endocytic vesicle membrane / response to virus / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G protein-coupled acetylcholine receptor signaling pathway / Cargo recognition for clathrin-mediated endocytosis / nervous system development / presynapse / Clathrin-mediated endocytosis / G alpha (i) signalling events / chemical synaptic transmission / postsynaptic membrane / cilium / ciliary basal body / G protein-coupled receptor signaling pathway / synapse / dendrite / nucleolus / Golgi apparatus / membrane / plasma membrane
Similarity search - Function
Muscarinic acetylcholine receptor M2 / Muscarinic acetylcholine receptor family / Rhopdopsin 7-helix transmembrane proteins / Rhodopsin 7-helix transmembrane proteins / 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) ...Muscarinic acetylcholine receptor M2 / Muscarinic acetylcholine receptor family / Rhopdopsin 7-helix transmembrane proteins / Rhodopsin 7-helix transmembrane proteins / 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) / Immunoglobulins / Up-down Bundle / Immunoglobulin-like / Sandwich / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Chem-2CU / Chem-IXO / Muscarinic acetylcholine receptor M2
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.7 Å
AuthorsKruse, A.C. / Ring, A.M. / Manglik, A. / Hu, J. / Hu, K. / Eitel, K. / Huebner, H. / Pardon, E. / Valant, C. / Sexton, P.M. ...Kruse, A.C. / Ring, A.M. / Manglik, A. / Hu, J. / Hu, K. / Eitel, K. / Huebner, H. / Pardon, E. / Valant, C. / Sexton, P.M. / Christopoulos, A. / Felder, C.C. / Gmeiner, P. / Steyaert, J. / Weis, W.I. / Garcia, K.C. / Wess, J. / Kobilka, B.K.
CitationJournal: Nature / Year: 2013
Title: Activation and allosteric modulation of a muscarinic acetylcholine receptor.
Authors: Kruse, A.C. / Ring, A.M. / Manglik, A. / Hu, J. / Hu, K. / Eitel, K. / Hubner, H. / Pardon, E. / Valant, C. / Sexton, P.M. / Christopoulos, A. / Felder, C.C. / Gmeiner, P. / Steyaert, J. / ...Authors: Kruse, A.C. / Ring, A.M. / Manglik, A. / Hu, J. / Hu, K. / Eitel, K. / Hubner, H. / Pardon, E. / Valant, C. / Sexton, P.M. / Christopoulos, A. / Felder, C.C. / Gmeiner, P. / Steyaert, J. / Weis, W.I. / Garcia, K.C. / Wess, J. / Kobilka, B.K.
History
DepositionSep 16, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 27, 2013Provider: repository / Type: Initial release
Revision 1.1Dec 4, 2013Group: Database references
Revision 1.2Dec 18, 2013Group: Database references
Revision 1.3Jul 5, 2017Group: Source and taxonomy / Category: entity_src_gen
Revision 1.4May 1, 2019Group: Data collection / Structure summary / Category: chem_comp / Item: _chem_comp.pdbx_synonyms
Revision 1.5Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.6Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature
Remark 650HELIX DETERMINATION METHOD: AUTHOR DETERMINED

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Muscarinic acetylcholine receptor M2
B: Nanobody 9-8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,0154
Polymers53,3802
Non-polymers6352
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2520 Å2
ΔGint-16 kcal/mol
Surface area18200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.032, 77.399, 163.822
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Muscarinic acetylcholine receptor M2


Mass: 39951.734 Da / Num. of mol.: 1 / Fragment: UNP residues 1-232,373-466 / Mutation: N0D, N1D, N4D, N7D, A373T, K374R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CHRM2 / Plasmid: PVL1392 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P08172
#2: Antibody Nanobody 9-8


Mass: 13428.396 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Plasmid: pMAL3CBN / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
#3: Chemical ChemComp-IXO / 4-(4,5-dihydro-1,2-oxazol-3-yloxy)-N,N,N-trimethylbut-2-yn-1-aminium / Iperoxo


Mass: 197.254 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N2O2
#4: Chemical ChemComp-2CU / 3-amino-5-chloro-N-cyclopropyl-4-methyl-6-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]thieno[2,3-b]pyridine-2-carboxamide / LY2119620 positive allosteric modulator of M2/M4 receptor


Mass: 437.944 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H24ClN5O3S
Has protein modificationY

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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: 3.51 Å3/Da / Density % sol: 64.91 %
Crystal growTemperature: 293 K / Method: lipidic cubic phase
Details: Reconstituted in 10:1 monoolein:cholesterol mix. Precipitant solution: 0.5 mM LY2119620, 10 - 20% PEG300, 100 mM HEPES pH 7.2 - 7.9, 1.2% 1,2,3-heptanetriol, and 20 - 80 mM EDTA pH 8.0, ...Details: Reconstituted in 10:1 monoolein:cholesterol mix. Precipitant solution: 0.5 mM LY2119620, 10 - 20% PEG300, 100 mM HEPES pH 7.2 - 7.9, 1.2% 1,2,3-heptanetriol, and 20 - 80 mM EDTA pH 8.0, Lipidic cubic phase, temperature 293K

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Data collection

DiffractionMean temperature: 77 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.033 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Apr 16, 2013 / Details: Mirrors
RadiationMonochromator: Double crystal cryo-cooled Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033 Å / Relative weight: 1
ReflectionResolution: 3.7→36 Å / Num. obs: 7871 / % possible obs: 93 % / Observed criterion σ(I): -3 / Redundancy: 4.8 % / Rmerge(I) obs: 0.195
Reflection shellResolution: 3.7→3.8 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.605 / Num. unique all: 644 / % possible all: 80.1

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
PHENIX(phenix.refine: dev_1241)refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4MQS

4mqs


Resolution: 3.7→36 Å / SU ML: 0.59 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 33.55 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.3014 780 9.91 %Random
Rwork0.2496 ---
obs0.2547 7867 92.94 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.7→36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3013 0 43 0 3056
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0043142
X-RAY DIFFRACTIONf_angle_d0.8114309
X-RAY DIFFRACTIONf_dihedral_angle_d14.1091047
X-RAY DIFFRACTIONf_chiral_restr0.06508
X-RAY DIFFRACTIONf_plane_restr0.003525
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.7-3.93150.36371100.3141043X-RAY DIFFRACTION84
3.9315-4.23470.38161240.28811164X-RAY DIFFRACTION93
4.2347-4.660.29751350.22581158X-RAY DIFFRACTION94
4.66-5.33250.25131330.21031202X-RAY DIFFRACTION95
5.3325-6.71140.39051340.28531229X-RAY DIFFRACTION96
6.7114-36.20160.24841440.23161291X-RAY DIFFRACTION95

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