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- PDB-5j9f: Human GAR transformylase in complex with GAR and (4-{[2-(2-Amino-... -

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Basic information

Entry
Database: PDB / ID: 5j9f
TitleHuman GAR transformylase in complex with GAR and (4-{[2-(2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)ethyl]amino}benzoyl)-L-glutamic acid (AGF183)
ComponentsTrifunctional purine biosynthetic protein adenosine-3
Keywordsligase/ligase inhibitor / gar transformylase / antifolate / 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 / GMP biosynthetic process / purine nucleotide 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, ATP-grasp (A) domain / 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. ...Phosphoribosylformylglycinamidine cyclo-ligase / Phosphoribosylglycinamide synthetase, ATP-grasp (A) domain / 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 / Formyl transferase, N-terminal 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. / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-83A / GLYCINAMIDE RIBONUCLEOTIDE / Trifunctional purine biosynthetic protein adenosine-3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsWong, J. / Deis, S.M. / Dann III, C.E.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)CA166711 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM094472 United States
CitationJournal: J.Med.Chem. / Year: 2016
Title: Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions via Cellular Uptake by Folate Receptor alpha and the Proton-Coupled Folate ...Title: Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions via Cellular Uptake by Folate Receptor alpha and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis.
Authors: Golani, L.K. / Wallace-Povirk, A. / Deis, S.M. / Wong, J. / Ke, J. / Gu, X. / Raghavan, S. / Wilson, M.R. / Li, X. / Polin, L. / de Waal, P.W. / White, K. / Kushner, J. / O'Connor, C. / Hou, ...Authors: Golani, L.K. / Wallace-Povirk, A. / Deis, S.M. / Wong, J. / Ke, J. / Gu, X. / Raghavan, S. / Wilson, M.R. / Li, X. / Polin, L. / de Waal, P.W. / White, K. / Kushner, J. / O'Connor, C. / Hou, Z. / Xu, H.E. / Melcher, K. / Dann, C.E. / Matherly, L.H. / Gangjee, A.
History
DepositionApr 9, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 10, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 21, 2016Group: Database references
Revision 1.2Sep 20, 2017Group: Author supporting evidence / Database references / Derived calculations
Category: citation / pdbx_audit_support / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Sep 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength / 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)23,4803
Polymers22,7531
Non-polymers7272
Water93752
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area610 Å2
ΔGint-5 kcal/mol
Surface area9340 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.386, 75.386, 101.293
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221

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Components

#1: Protein Trifunctional purine biosynthetic protein adenosine-3


Mass: 22753.088 Da / Num. of mol.: 1 / Fragment: unp residues 808-1010 / Mutation: Q905A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GART, PGFT, PRGS / Plasmid: pET22B / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta(DE3)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: isolated from a natural source / Formula: C7H13N2O8P
#3: Chemical ChemComp-83A / N-(4-{[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)ethyl]amino}benzene-1-carbonyl)-L-glutamic acid / antifolate AGF183


Mass: 442.425 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H22N6O6
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 52 / 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: 3.64 Å3/Da / Density % sol: 66.23 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.1 M Tris (pH 7.5), 0.333 mM NaCl, 18% polyethylene glycol (PEG) 3350, and 2% PEG 400

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Dec 9, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→40.017 Å / Num. obs: 22067 / % possible obs: 100 % / Redundancy: 5.4 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 13
Reflection shellResolution: 2.1→2.16 Å / Redundancy: 5.5 % / Rmerge(I) obs: 0.75 / Mean I/σ(I) obs: 2.6 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ZZ1

4zz1


Resolution: 2.1→40.02 Å / SU ML: 0.22 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 20.41 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.213 1825 9.15 %
Rwork0.174 --
obs0.177 19940 99.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.1→40.02 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1499 0 50 52 1601
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0141574
X-RAY DIFFRACTIONf_angle_d1.4762139
X-RAY DIFFRACTIONf_dihedral_angle_d13.722564
X-RAY DIFFRACTIONf_chiral_restr0.072256
X-RAY DIFFRACTIONf_plane_restr0.006271
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.15680.27231390.22591361X-RAY DIFFRACTION100
2.1568-2.22030.26371390.19661374X-RAY DIFFRACTION100
2.2203-2.29190.22331350.1911373X-RAY DIFFRACTION100
2.2919-2.37380.22581380.17611377X-RAY DIFFRACTION100
2.3738-2.46890.21491380.18461371X-RAY DIFFRACTION100
2.4689-2.58120.21841350.18161381X-RAY DIFFRACTION100
2.5812-2.71730.26521350.19451384X-RAY DIFFRACTION100
2.7173-2.88750.25681410.20811384X-RAY DIFFRACTION100
2.8875-3.11030.27011420.20631400X-RAY DIFFRACTION100
3.1103-3.42320.23261480.20091395X-RAY DIFFRACTION100
3.4232-3.91820.19431420.16731396X-RAY DIFFRACTION100
3.9182-4.9350.15761420.12851419X-RAY DIFFRACTION100
4.935-40.02420.17711510.14261500X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: 31.716 Å / Origin y: -19.1007 Å / Origin z: -22.6729 Å
111213212223313233
T0.173 Å2-0.0108 Å20.0318 Å2-0.1388 Å20.0117 Å2--0.1817 Å2
L1.0309 °20.1305 °2-0.6686 °2-0.8954 °2-0.23 °2--1.4334 °2
S0.1441 Å °0.0173 Å °0.2381 Å °0.0145 Å °-0.0167 Å °-0.0368 Å °-0.1956 Å °0.0272 Å °0.0058 Å °
Refinement TLS groupSelection details: ALL

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