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- PDB-5uz0: Crystal structure of AICARFT bound to an antifolate -

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Basic information

Entry
Database: PDB / ID: 5uz0
TitleCrystal structure of AICARFT bound to an antifolate
ComponentsBifunctional purine biosynthesis protein PURH
KeywordsTRANSFERASE / HYDROLASE / AICAR / AICARFT / AMZ
Function / homology
Function and homology information


phosphoribosylaminoimidazolecarboxamide formyltransferase / phosphoribosylaminoimidazolecarboxamide formyltransferase activity / IMP cyclohydrolase / IMP cyclohydrolase activity / 'de novo' XMP biosynthetic process / brainstem development / Purine ribonucleoside monophosphate biosynthesis / 'de novo' AMP biosynthetic process / GMP biosynthetic process / cellular response to interleukin-7 ...phosphoribosylaminoimidazolecarboxamide formyltransferase / phosphoribosylaminoimidazolecarboxamide formyltransferase activity / IMP cyclohydrolase / IMP cyclohydrolase activity / 'de novo' XMP biosynthetic process / brainstem development / Purine ribonucleoside monophosphate biosynthesis / 'de novo' AMP biosynthetic process / GMP biosynthetic process / cellular response to interleukin-7 / nucleobase-containing compound metabolic process / dihydrofolate metabolic process / 'de novo' IMP biosynthetic process / Signaling by ALK fusions and activated point mutants / response to inorganic substance / animal organ regeneration / tetrahydrofolate biosynthetic process / cerebellum development / cerebral cortex development / cadherin binding / protein homodimerization activity / extracellular exosome / membrane / plasma membrane / cytosol
Similarity search - Function
Helix Hairpins - #440 / AICAR transformylase, insert domain superfamily / AICAR transformylase, duplication domain / AICAR transformylase, duplicated domain superfamily / AICARFT/IMPCHase bienzyme / Bifunctional purine biosynthesis protein PurH-like / AICARFT/IMPCHase bienzyme / Methylglyoxal synthase-like domain / MGS-like domain profile. / Methylglyoxal synthase-like domain ...Helix Hairpins - #440 / AICAR transformylase, insert domain superfamily / AICAR transformylase, duplication domain / AICAR transformylase, duplicated domain superfamily / AICARFT/IMPCHase bienzyme / Bifunctional purine biosynthesis protein PurH-like / AICARFT/IMPCHase bienzyme / Methylglyoxal synthase-like domain / MGS-like domain profile. / Methylglyoxal synthase-like domain / Methylglyoxal synthase-like domain superfamily / MGS-like domain / MGS-like domain / Cytidine Deaminase; domain 2 / Cytidine deaminase-like / Helix Hairpins / Rossmann fold / Orthogonal Bundle / 3-Layer(aba) Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-8US / AMINOIMIDAZOLE 4-CARBOXAMIDE RIBONUCLEOTIDE / Bifunctional purine biosynthesis protein ATIC
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.79 Å
AuthorsAtwell, S. / Wang, Y. / Fales, K.R. / Clawson, D. / Wang, J.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery of N-(6-Fluoro-1-oxo-1,2-dihydroisoquinolin-7-yl)-5-[(3R)-3-hydroxypyrrolidin-1-yl]thiophene-2-sulfonamide (LSN 3213128), a Potent and Selective Nonclassical Antifolate ...Title: Discovery of N-(6-Fluoro-1-oxo-1,2-dihydroisoquinolin-7-yl)-5-[(3R)-3-hydroxypyrrolidin-1-yl]thiophene-2-sulfonamide (LSN 3213128), a Potent and Selective Nonclassical Antifolate Aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase (AICARFT) Inhibitor Effective at Tumor Suppression in a Cancer Xenograft Model.
Authors: Fales, K.R. / Njoroge, F.G. / Brooks, H.B. / Thibodeaux, S. / Torrado, A. / Si, C. / Toth, J.L. / Mc Cowan, J.R. / Roth, K.D. / Thrasher, K.J. / Frimpong, K. / Lee, M.R. / Dally, R.D. / ...Authors: Fales, K.R. / Njoroge, F.G. / Brooks, H.B. / Thibodeaux, S. / Torrado, A. / Si, C. / Toth, J.L. / Mc Cowan, J.R. / Roth, K.D. / Thrasher, K.J. / Frimpong, K. / Lee, M.R. / Dally, R.D. / Shepherd, T.A. / Durham, T.B. / Margolis, B.J. / Wu, Z. / Wang, Y. / Atwell, S. / Wang, J. / Hui, Y.H. / Meier, T.I. / Konicek, S.A. / Geeganage, S.
History
DepositionFeb 24, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 10, 2018Provider: repository / Type: Initial release
Revision 1.1Mar 6, 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

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Assembly

Deposited unit
A: Bifunctional purine biosynthesis protein PURH
B: Bifunctional purine biosynthesis protein PURH
C: Bifunctional purine biosynthesis protein PURH
D: Bifunctional purine biosynthesis protein PURH
hetero molecules


Theoretical massNumber of molelcules
Total (without water)267,27819
Polymers263,1764
Non-polymers4,10315
Water10,737596
1
A: Bifunctional purine biosynthesis protein PURH
B: Bifunctional purine biosynthesis protein PURH
hetero molecules


Theoretical massNumber of molelcules
Total (without water)133,4709
Polymers131,5882
Non-polymers1,8827
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area15180 Å2
ΔGint-68 kcal/mol
Surface area42160 Å2
MethodPISA
2
C: Bifunctional purine biosynthesis protein PURH
D: Bifunctional purine biosynthesis protein PURH
hetero molecules


Theoretical massNumber of molelcules
Total (without water)133,80810
Polymers131,5882
Non-polymers2,2208
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area15870 Å2
ΔGint-68 kcal/mol
Surface area41430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.797, 105.121, 105.646
Angle α, β, γ (deg.)113.48, 99.42, 95.52
Int Tables number1
Space group name H-MP1

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Components

#1: Protein
Bifunctional purine biosynthesis protein PURH


Mass: 65793.922 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ATIC, PURH, OK/SW-cl.86 / Production host: Escherichia coli (E. coli)
References: UniProt: P31939, phosphoribosylaminoimidazolecarboxamide formyltransferase, IMP cyclohydrolase
#2: Chemical
ChemComp-AMZ / AMINOIMIDAZOLE 4-CARBOXAMIDE RIBONUCLEOTIDE / AICAR / AICA ribonucleotide


Mass: 338.211 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C9H15N4O8P
#3: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#4: Chemical
ChemComp-8US / N-(6-fluoro-1-oxo-1,2-dihydroisoquinolin-7-yl)-5-[(3R)-3-hydroxypyrrolidin-1-yl]thiophene-2-sulfonamide


Mass: 409.455 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H16FN3O4S2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 596 / 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: 2.32 Å3/Da / Density % sol: 47.02 %
Crystal growTemperature: 281 K / Method: vapor diffusion, sitting drop
Details: 100mM Hepes pH 7.3, 5% MPD, 28% PEG 3350, 200mM Magnesium Chloride

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97949 Å
DetectorType: RAYONIX MX325HE / Detector: CCD / Date: Oct 2, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 1.79→30 Å / Num. obs: 213181 / % possible obs: 95.64 % / Redundancy: 3.7 % / Biso Wilson estimate: 16.22 Å2 / Net I/σ(I): 9.9

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.79→18.04 Å / Cor.coef. Fo:Fc: 0.9039 / Cor.coef. Fo:Fc free: 0.8838 / SU R Cruickshank DPI: 0.135 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.13 / SU Rfree Blow DPI: 0.117 / SU Rfree Cruickshank DPI: 0.121
RfactorNum. reflection% reflectionSelection details
Rfree0.2247 10759 5.05 %RANDOM
Rwork0.2024 ---
obs0.2035 213181 95.64 %-
Displacement parametersBiso mean: 17.22 Å2
Baniso -1Baniso -2Baniso -3
1--3.6665 Å2-1.1868 Å25.0511 Å2
2--2.373 Å20.8091 Å2
3---1.2935 Å2
Refine analyzeLuzzati coordinate error obs: 0.223 Å
Refinement stepCycle: 1 / Resolution: 1.79→18.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms17951 0 266 596 18813
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0118567HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0625259HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d6388SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes427HARMONIC2
X-RAY DIFFRACTIONt_gen_planes2712HARMONIC5
X-RAY DIFFRACTIONt_it18567HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.37
X-RAY DIFFRACTIONt_other_torsion15.55
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion2487SEMIHARMONIC5
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_contact22193SEMIHARMONIC4
LS refinement shellResolution: 1.79→1.84 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2347 736 4.93 %
Rwork0.2105 14181 -
all0.2117 14917 -
obs--95.64 %

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