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- PDB-7e5e: Crystal structure of GDP-bound GNAS in complex with the cyclic pe... -

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Basic information

Entry
Database: PDB / ID: 7e5e
TitleCrystal structure of GDP-bound GNAS in complex with the cyclic peptide inhibitor GD20
Components
  • GD20
  • Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
KeywordsSIGNALING PROTEIN / G protein / GNAS / adenylyl cyclase / inactive state / inhibitor / mRNA display / RaPID / cyclic peptide / GD20
Function / homology
Function and homology information


PKA activation in glucagon signalling / hair follicle placode formation / intracellular transport / D1 dopamine receptor binding / developmental growth / Hedgehog 'off' state / positive regulation of cAMP-mediated signaling / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / adenylate cyclase activator activity ...PKA activation in glucagon signalling / hair follicle placode formation / intracellular transport / D1 dopamine receptor binding / developmental growth / Hedgehog 'off' state / positive regulation of cAMP-mediated signaling / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / adenylate cyclase activator activity / trans-Golgi network membrane / G-protein beta/gamma-subunit complex binding / bone development / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / adenylate cyclase-activating G protein-coupled receptor signaling pathway / platelet aggregation / Glucagon-type ligand receptors / cognition / Vasopressin regulates renal water homeostasis via Aquaporins / positive regulation of GTPase activity / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / GPER1 signaling / heterotrimeric G-protein complex / sensory perception of smell / positive regulation of cold-induced thermogenesis / G alpha (i) signalling events / G alpha (s) signalling events / GTPase activity / GTP binding / extracellular exosome / membrane / metal ion binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
G-protein alpha subunit, group S / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
GUANOSINE-5'-DIPHOSPHATE / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsHu, Q. / Dai, S. / Shokat, K.M.
Funding support United States, 1items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Cell / Year: 2022
Title: State-selective modulation of heterotrimeric G alpha s signaling with macrocyclic peptides.
Authors: Dai, S.A. / Hu, Q. / Gao, R. / Blythe, E.E. / Touhara, K.K. / Peacock, H. / Zhang, Z. / von Zastrow, M. / Suga, H. / Shokat, K.M.
History
DepositionFeb 18, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 2, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 12, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 2, 2022Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first
Revision 1.3Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
B: Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
C: Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
D: Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
E: GD20
F: GD20
G: GD20
H: GD20
hetero molecules


Theoretical massNumber of molelcules
Total (without water)171,38316
Polymers169,4688
Non-polymers1,9158
Water5,927329
1
A: Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
E: GD20
hetero molecules


  • defined by author&software
  • Evidence: surface plasmon resonance, SPR data shows that the binding affinity (Kd) between GNAS and GD20 is 9.14 nM. Besides, in the crystal structure, each GNAS molecule has one molecule of GD20 binds to it.
  • 42.8 kDa, 2 polymers
  • Search similar-shape structures of this assembly by Omokage search (details)
Theoretical massNumber of molelcules
Total (without water)42,8464
Polymers42,3672
Non-polymers4792
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2630 Å2
ΔGint-31 kcal/mol
Surface area17430 Å2
MethodPISA
2
B: Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
F: GD20
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,8464
Polymers42,3672
Non-polymers4792
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2510 Å2
ΔGint-31 kcal/mol
Surface area16670 Å2
MethodPISA
3
C: Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
G: GD20
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,8464
Polymers42,3672
Non-polymers4792
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2620 Å2
ΔGint-31 kcal/mol
Surface area17220 Å2
MethodPISA
4
D: Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
H: GD20
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,8464
Polymers42,3672
Non-polymers4792
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2640 Å2
ΔGint-31 kcal/mol
Surface area16560 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.105, 81.771, 76.912
Angle α, β, γ (deg.)81.266, 83.844, 90.698
Int Tables number1
Space group name H-MP1
Space group name HallP1
Symmetry operation#1: x,y,z

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Components

#1: Protein
Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Adenylate cyclase-stimulating G alpha protein


Mass: 40512.871 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP / Production host: Escherichia coli (E. coli) / References: UniProt: P63092
#2: Protein/peptide
GD20


Mass: 1854.182 Da / Num. of mol.: 4 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: Chemical
ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE / Guanosine diphosphate


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: GDP, energy-carrying molecule*YM
#4: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: Cl / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 329 / Source method: isolated from a natural source / Formula: H2O
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: 2.18 Å3/Da / Density % sol: 43.62 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.2 / Details: 0.1M Tris 8.2, 26% PEG 4000, 0.8M LiCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 0.999965 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 14, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999965 Å / Relative weight: 1
ReflectionResolution: 1.95→50 Å / Num. obs: 95974 / % possible obs: 97 % / Redundancy: 3.4 % / Biso Wilson estimate: 19.71 Å2 / CC1/2: 0.991 / Rmerge(I) obs: 0.081 / Rpim(I) all: 0.059 / Net I/σ(I): 11.4
Reflection shellResolution: 1.95→1.98 Å / Rmerge(I) obs: 1.202 / Mean I/σ(I) obs: 0.815 / Num. unique obs: 4489 / CC1/2: 0.422 / Rpim(I) all: 0.762

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
HKL-2000data reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6AU6

6au6


Resolution: 1.95→48.54 Å / SU ML: 0.2546 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 29.8601
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2582 4043 4.92 %
Rwork0.2176 78155 -
obs0.2196 82198 80.74 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 29.01 Å2
Refinement stepCycle: LAST / Resolution: 1.95→48.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11295 0 116 329 11740
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.003611661
X-RAY DIFFRACTIONf_angle_d0.692415807
X-RAY DIFFRACTIONf_chiral_restr0.04631714
X-RAY DIFFRACTIONf_plane_restr0.00352044
X-RAY DIFFRACTIONf_dihedral_angle_d18.61194311
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.95-1.970.4425160.299374X-RAY DIFFRACTION11.33
1.97-1.990.3914340.2751648X-RAY DIFFRACTION19.2
1.99-2.020.2798480.285866X-RAY DIFFRACTION26.18
2.02-2.050.2942620.26451047X-RAY DIFFRACTION32.03
2.05-2.070.3526720.26281338X-RAY DIFFRACTION39.08
2.07-2.10.3136890.27031519X-RAY DIFFRACTION46.61
2.1-2.130.3161950.26041917X-RAY DIFFRACTION57.42
2.13-2.170.28091150.25692345X-RAY DIFFRACTION70.25
2.17-2.20.31781490.25042905X-RAY DIFFRACTION86.54
2.2-2.240.3081580.25213128X-RAY DIFFRACTION93.75
2.24-2.280.29861690.25753202X-RAY DIFFRACTION96.26
2.28-2.330.29311620.24273254X-RAY DIFFRACTION96.5
2.33-2.370.31011540.23823196X-RAY DIFFRACTION97.36
2.37-2.430.30461620.25033310X-RAY DIFFRACTION97.39
2.43-2.480.32311520.24553262X-RAY DIFFRACTION97.71
2.48-2.540.27881530.24423274X-RAY DIFFRACTION97.52
2.54-2.610.28751820.25353266X-RAY DIFFRACTION97.68
2.61-2.690.3281870.25093210X-RAY DIFFRACTION97.9
2.69-2.780.3281800.25713293X-RAY DIFFRACTION98.11
2.78-2.880.3091540.26323287X-RAY DIFFRACTION98.06
2.88-2.990.28851580.24563282X-RAY DIFFRACTION98.4
2.99-3.130.29621810.2343270X-RAY DIFFRACTION98.29
3.13-3.290.27211790.23323274X-RAY DIFFRACTION98.63
3.29-3.50.23741930.21253279X-RAY DIFFRACTION98.58
3.5-3.770.21721860.1883284X-RAY DIFFRACTION98.66
3.77-4.150.19841610.17273341X-RAY DIFFRACTION98.79
4.15-4.750.18531730.15713277X-RAY DIFFRACTION98.94
4.75-5.980.18431550.17373329X-RAY DIFFRACTION99.17
5.98-48.540.20071640.17163178X-RAY DIFFRACTION95.16

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