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- PDB-7jg0: Human GAR transformylase in complex with GAR substrate and AGF102... -

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Basic information

Entry
Database: PDB / ID: 7jg0
TitleHuman GAR transformylase in complex with GAR substrate and AGF102 inhibitor
ComponentsTrifunctional purine biosynthetic protein adenosine-3
KeywordsLIGASE/LIGASE INHIBITOR / GARFTase / formyltransferase / transformylase / enzyme protein inhibitor / metabolism / alpha beta protein / Rossman fold / LIGASE / LIGASE-LIGASE INHIBITOR complex
Function / homology
Function and homology information


phosphoribosylformylglycinamidine cyclo-ligase / phosphoribosylformylglycinamidine cyclo-ligase activity / adenine biosynthetic process / phosphoribosylamine-glycine ligase / phosphoribosylamine-glycine ligase activity / phosphoribosylglycinamide formyltransferase 1 / purine ribonucleoside monophosphate biosynthetic process / phosphoribosylglycinamide formyltransferase activity / 'de novo' XMP biosynthetic process / brainstem development ...phosphoribosylformylglycinamidine cyclo-ligase / phosphoribosylformylglycinamidine cyclo-ligase activity / adenine biosynthetic process / phosphoribosylamine-glycine ligase / phosphoribosylamine-glycine ligase activity / phosphoribosylglycinamide formyltransferase 1 / purine ribonucleoside monophosphate biosynthetic process / phosphoribosylglycinamide formyltransferase activity / 'de novo' XMP biosynthetic process / brainstem development / Purine ribonucleoside monophosphate biosynthesis / glycine metabolic process / 'de novo' AMP biosynthetic process / purine nucleotide biosynthetic process / GMP biosynthetic process / 'de novo' IMP biosynthetic process / tetrahydrofolate biosynthetic process / cerebellum development / cerebral cortex development / extracellular exosome / ATP binding / metal ion binding / cytosol
Similarity search - Function
Phosphoribosylformylglycinamidine cyclo-ligase / Phosphoribosylglycinamide synthetase / Phosphoribosylglycinamide synthetase, conserved site / Phosphoribosylglycinamide synthetase, C-domain / Phosphoribosylglycinamide synthetase, N-terminal / Phosphoribosylglycinamide synthetase, C-domain superfamily / Phosphoribosylglycinamide synthetase, C domain / Phosphoribosylglycinamide synthetase, N domain / Phosphoribosylglycinamide synthetase signature. / Phosphoribosylglycinamide synthetase, C domain ...Phosphoribosylformylglycinamidine cyclo-ligase / Phosphoribosylglycinamide synthetase / Phosphoribosylglycinamide synthetase, conserved site / Phosphoribosylglycinamide synthetase, C-domain / Phosphoribosylglycinamide synthetase, N-terminal / Phosphoribosylglycinamide synthetase, C-domain superfamily / Phosphoribosylglycinamide synthetase, C domain / Phosphoribosylglycinamide synthetase, N domain / Phosphoribosylglycinamide synthetase signature. / Phosphoribosylglycinamide synthetase, C domain / Phosphoribosylglycinamide synthetase, ATP-grasp (A) domain / Phosphoribosylglycinamide synthetase, ATP-grasp (A) domain / Phosphoribosylglycinamide formyltransferase / Phosphoribosylglycinamide synthetase, ATP-grasp (A) domain / PurM-like, N-terminal domain / AIR synthase related protein, N-terminal domain / Phosphoribosylglycinamide formyltransferase, active site / Phosphoribosylglycinamide formyltransferase active site. / PurM-like, C-terminal domain / PurM-like, C-terminal domain superfamily / PurM-like, N-terminal domain superfamily / AIR synthase related protein, C-terminal domain / Formyl transferase, N-terminal / Formyl transferase / Formyl transferase, N-terminal domain superfamily / Rudiment single hybrid motif / ATP-grasp fold, subdomain 1 / Pre-ATP-grasp domain superfamily / ATP-grasp fold / ATP-grasp fold profile.
Similarity search - Domain/homology
GLYCINAMIDE RIBONUCLEOTIDE / Chem-V97 / Trifunctional purine biosynthetic protein adenosine-3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.984 Å
AuthorsWong-Roushar, J. / Dann III, C.E.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 CA166711 United States
CitationJournal: Bioorg.Med.Chem. / Year: 2021
Title: Discovery of 6-substituted thieno[2,3-d]pyrimidine analogs as dual inhibitors of glycinamide ribonucleotide formyltransferase and 5-aminoimidazole-4-carboxamide ribonucleotide ...Title: Discovery of 6-substituted thieno[2,3-d]pyrimidine analogs as dual inhibitors of glycinamide ribonucleotide formyltransferase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase in de novo purine nucleotide biosynthesis in folate receptor expressing human tumors
Authors: Wallace-Povirk, A. / Tong, N. / Wong-Roushar, J. / O'Connor, C. / Zhou, X. / Hou, Z. / Bao, X. / Garcia, G.E. / Li, J. / Kim, S. / Dann, C.E. / Matherly, L.H. / Gangjee, A.
History
DepositionJul 18, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 31, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Trifunctional purine biosynthetic protein adenosine-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,5733
Polymers22,8101
Non-polymers7632
Water2,252125
1
A: Trifunctional purine biosynthetic protein adenosine-3
hetero molecules

A: Trifunctional purine biosynthetic protein adenosine-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,1466
Polymers45,6202
Non-polymers1,5254
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation6_555-x,-x+y,-z+2/31
Buried area2760 Å2
ΔGint-19 kcal/mol
Surface area17080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.232, 75.232, 99.955
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221

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Components

#1: Protein Trifunctional purine biosynthetic protein adenosine-3


Mass: 22810.139 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GART, PGFT, PRGS / Plasmid: pHis-parallel / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / Variant (production host): Rosetta pLysS
References: UniProt: P22102, phosphoribosylamine-glycine ligase, phosphoribosylformylglycinamidine cyclo-ligase, phosphoribosylglycinamide formyltransferase 1
#2: Chemical ChemComp-GAR / GLYCINAMIDE RIBONUCLEOTIDE


Mass: 284.160 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H13N2O8P
#3: Chemical ChemComp-V97 / N-{5-[4-(2-amino-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-6-yl)butyl]thiophene-2-carbonyl}-L-glutamic acid


Mass: 478.542 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H22N4O6S2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 125 / 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: 3.58 Å3/Da / Density % sol: 65.69 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.1 M Tris (pH 7.5), 0.222 M NaCl, 22% polyethylene glycol (PEG) 4000, and 2% PEG 400

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 4.2.2 / Wavelength: 1 Å
DetectorType: RDI CMOS_8M / Detector: CMOS / Date: Apr 11, 2019
RadiationMonochromator: GRAPHITE / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.98→39.655 Å / Num. obs: 22671 / % possible obs: 97.8 % / Redundancy: 8.8 % / Biso Wilson estimate: 26.91 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.092 / Rpim(I) all: 0.033 / Rrim(I) all: 0.098 / Net I/σ(I): 18.1
Reflection shellResolution: 1.98→2.05 Å / Rmerge(I) obs: 1.002 / Mean I/σ(I) obs: 1.1 / Num. unique obs: 20977 / CC1/2: 0.483 / Rpim(I) all: 0.561 / Rrim(I) all: 1.157 / % possible all: 86

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIXv1.13refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5J9F

5j9f


Resolution: 1.984→39.655 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 22.56 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2116 1087 4.79 %
Rwork0.1829 21584 -
obs0.1844 22671 97.75 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 107.09 Å2 / Biso mean: 34.7239 Å2 / Biso min: 13.89 Å2
Refinement stepCycle: final / Resolution: 1.984→39.655 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1503 0 63 125 1691
Biso mean--42.02 41.49 -
Num. residues----200
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.984-2.07390.36031100.2942232686
2.0739-2.18330.24751350.2285261397
2.1833-2.320.30221320.21512733100
2.32-2.49910.22931080.18532764100
2.4991-2.75060.22451570.2012700100
2.7506-3.14840.22331600.1972757100
3.1484-3.96610.19141290.16122794100
3.9661-39.6550.16991560.15262897100
Refinement TLS params.Method: refined / Origin x: -31.8263 Å / Origin y: 19.0061 Å / Origin z: 27.7558 Å
111213212223313233
T0.2015 Å20.0063 Å2-0.0266 Å2-0.1636 Å2-0.0215 Å2--0.2147 Å2
L1.8626 °20.5132 °20.9262 °2-1.2478 °20.4006 °2--2.0662 °2
S0.1453 Å °0.1366 Å °-0.3668 Å °-0.0138 Å °0.0102 Å °0.0284 Å °0.297 Å °-0.0142 Å °-0.1035 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA807 - 1200
2X-RAY DIFFRACTION1allC1 - 125

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