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- PDB-6nfo: CYCLIC GMP-AMP SYNTHASE in complex with compound 20 inhibitor: 7-... -

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Basic information

Entry
Database: PDB / ID: 6nfo
TitleCYCLIC GMP-AMP SYNTHASE in complex with compound 20 inhibitor: 7-hydroxy-N-[(2S)-1-hydroxypropan-2-yl]-5-phenylpyrazolo[1,5-a]pyrimidine-3-carboxamide
ComponentsCYCLIC GMP-AMP SYNTHASE
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / cGAS / STING / cGAMP / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


cyclic GMP-AMP synthase / 2',3'-cyclic GMP-AMP synthase activity / STING mediated induction of host immune responses / paracrine signaling / poly-ADP-D-ribose modification-dependent protein binding / regulation of immunoglobulin production / cGAS/STING signaling pathway / pattern recognition receptor signaling pathway / regulation of T cell activation / cytoplasmic pattern recognition receptor signaling pathway ...cyclic GMP-AMP synthase / 2',3'-cyclic GMP-AMP synthase activity / STING mediated induction of host immune responses / paracrine signaling / poly-ADP-D-ribose modification-dependent protein binding / regulation of immunoglobulin production / cGAS/STING signaling pathway / pattern recognition receptor signaling pathway / regulation of T cell activation / cytoplasmic pattern recognition receptor signaling pathway / negative regulation of cGAS/STING signaling pathway / cGMP-mediated signaling / cellular response to exogenous dsRNA / positive regulation of type I interferon production / negative regulation of double-strand break repair via homologous recombination / nucleosome binding / positive regulation of defense response to virus by host / phosphatidylinositol-4,5-bisphosphate binding / activation of innate immune response / cAMP-mediated signaling / molecular condensate scaffold activity / determination of adult lifespan / positive regulation of cellular senescence / site of double-strand break / double-stranded DNA binding / defense response to virus / nuclear body / DNA repair / innate immune response / DNA damage response / chromatin binding / GTP binding / protein homodimerization activity / DNA binding / nucleoplasm / ATP binding / nucleus / metal ion binding / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Beta Polymerase; domain 2 - #90 / Poly(a)-polymerase, middle domain - #40 / Poly(a)-polymerase, middle domain / Mab-21-like, nucleotidyltransferase domain / Mab-21-like, HhH/H2TH-like domain / Mab-21 protein HhH/H2TH-like domain / Mab-21 protein nucleotidyltransferase domain / Mab-21-like / Mab-21 / Beta Polymerase; domain 2 ...Beta Polymerase; domain 2 - #90 / Poly(a)-polymerase, middle domain - #40 / Poly(a)-polymerase, middle domain / Mab-21-like, nucleotidyltransferase domain / Mab-21-like, HhH/H2TH-like domain / Mab-21 protein HhH/H2TH-like domain / Mab-21 protein nucleotidyltransferase domain / Mab-21-like / Mab-21 / Beta Polymerase; domain 2 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-KKM / Cyclic GMP-AMP synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.93 Å
AuthorsHall, J.
CitationJournal: to be published
Title: Discovery of a high affinity inhibitor of cGAS
Authors: Hall, J.
History
DepositionDec 20, 2018Deposition site: RCSB / Processing site: RCSB
SupersessionJan 23, 2019ID: 5V8J
Revision 1.0Jan 23, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CYCLIC GMP-AMP SYNTHASE
B: CYCLIC GMP-AMP SYNTHASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)85,5656
Polymers84,8102
Non-polymers7554
Water48627
1
A: CYCLIC GMP-AMP SYNTHASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,7833
Polymers42,4051
Non-polymers3782
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: CYCLIC GMP-AMP SYNTHASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,7833
Polymers42,4051
Non-polymers3782
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)218.796, 45.999, 90.339
Angle α, β, γ (deg.)90.00, 111.64, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein CYCLIC GMP-AMP SYNTHASE / h-cGAS / 2'3'-cGAMP synthase / Mab-21 domain-containing protein 1


Mass: 42404.906 Da / Num. of mol.: 2 / Fragment: UNP RESIDUES 161-522
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CGAS, C6orf150, MB21D1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q8N884, cyclic GMP-AMP synthase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-KKM / 7-hydroxy-N-[(2S)-1-hydroxypropan-2-yl]-5-phenylpyrazolo[1,5-a]pyrimidine-3-carboxamide


Mass: 312.323 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H16N4O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 27 / Source method: isolated from a natural source / Formula: H2O

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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: 2.49 Å3/Da / Density % sol: 50.63 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: PROTEIN WAS CONCENTRATED TO 6 MG/ML, AND THEN MIXED AT A 2:1 RATIO WITH PEG 3350 (18-20% V/V), 0.2 M AMMONIUM CITRATE (PH 7) IN A SITTING DROP WELL AT 277 K. CRYOPROTECTANT WAS MADE USING ...Details: PROTEIN WAS CONCENTRATED TO 6 MG/ML, AND THEN MIXED AT A 2:1 RATIO WITH PEG 3350 (18-20% V/V), 0.2 M AMMONIUM CITRATE (PH 7) IN A SITTING DROP WELL AT 277 K. CRYOPROTECTANT WAS MADE USING MOTHER LIQUOR AT A FINAL CONCENTRATION OF 23% PEG 3350, VAPOR DIFFUSION, SITTING DROP

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Oct 1, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.93→83.97 Å / Num. obs: 18440 / % possible obs: 100 % / Redundancy: 5 % / Biso Wilson estimate: 74.48 Å2 / Net I/σ(I): 14.7
Reflection shellResolution: 2.93→3.11 Å

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Processing

Software
NameVersionClassification
Aimlessdata reduction
SCALAdata scaling
REFMACphasing
BUSTER2.11.7refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.93→83.97 Å / Cor.coef. Fo:Fc: 0.918 / Cor.coef. Fo:Fc free: 0.905 / Rfactor Rfree error: 0.02 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.357
RfactorNum. reflection% reflectionSelection details
Rfree0.231 942 5.11 %RANDOM
Rwork0.21 ---
obs0.211 18429 100 %-
Displacement parametersBiso mean: 68.1 Å2
Baniso -1Baniso -2Baniso -3
1--6.1269 Å20 Å2-9.947 Å2
2---3.3273 Å20 Å2
3---9.4542 Å2
Refine analyzeLuzzati coordinate error obs: 0.4 Å
Refinement stepCycle: LAST / Resolution: 2.93→83.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5372 0 48 27 5447
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015563HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.157551HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1857SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes122HARMONIC2
X-RAY DIFFRACTIONt_gen_planes810HARMONIC5
X-RAY DIFFRACTIONt_it5563HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.5
X-RAY DIFFRACTIONt_other_torsion21.55
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion738SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact6077SEMIHARMONIC4
LS refinement shellResolution: 2.93→3.11 Å / Rfactor Rfree error: 0 / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.28 146 4.95 %
Rwork0.263 2803 -
all0.263 2949 -
obs--100 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.981-0.3397-0.04181.7381-0.28391.84730.0496-0.0521-0.06060.0289-0.0612-0.3211-0.05940.35290.0116-0.0193-0.2205-0.0121-0.11170.0124-0.1553-30.993212.1787-21.3917
22.3130.0179-0.25552.26420.10951.797-0.0922-0.02050.13780.15530.1543-0.47420.08750.3766-0.0621-0.04850.2037-0.0254-0.1322-0.017-0.1118-30.86262.408221.3637
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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