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Basic information

Entry
Database: PDB / ID: 4m5j
TitleThe Identification, Analysis and Structure-Based Development of Novel Inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase
Components2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / FOLATE BIOSYNTHESIS / Diphosphotransferases / PTERIN / ATP binding / Inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase / 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase activity / folic acid biosynthetic process / tetrahydrofolate biosynthetic process / kinase activity / magnesium ion binding / ATP binding
Similarity search - Function
7,8-dihydro-6-hydroxymethylpterin-pyrophosphokinase signature. / 7,8-Dihydro-6-hydroxymethylpterin-pyrophosphokinase HPPK / 7,8-Dihydro-6-hydroxymethylpterin-pyrophosphokinase, HPPK / 7,8-Dihydro-6-hydroxymethylpterin-pyrophosphokinase HPPK superfamily / 7,8-dihydro-6-hydroxymethylpterin-pyrophosphokinase (HPPK) / Alpha-Beta Plaits / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
DIPHOSPHOMETHYLPHOSPHONIC ACID ADENOSYL ESTER / Chem-YH5 / 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase
Similarity search - Component
Biological speciesEscherichia coli (E. coli)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.696 Å
AuthorsYun, M. / Hoagland, D. / Kumar, G. / Waddell, B. / Rock, C.O. / Lee, R.E. / White, S.W.
CitationJournal: Bioorg.Med.Chem. / Year: 2014
Title: The identification, analysis and structure-based development of novel inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase.
Authors: Yun, M.K. / Hoagland, D. / Kumar, G. / Waddell, M.B. / Rock, C.O. / Lee, R.E. / White, S.W.
History
DepositionAug 8, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 2, 2014Provider: repository / Type: Initial release
Revision 1.1Apr 16, 2014Group: Database references
Revision 1.2Dec 14, 2016Group: Non-polymer description
Revision 1.3Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,3367
Polymers18,3801
Non-polymers9566
Water1,62190
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)36.458, 58.264, 38.374
Angle α, β, γ (deg.)90.00, 113.76, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 1 molecules A

#1: Protein 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase / 6-hydroxymethyl-7 / 8-dihydropterin pyrophosphokinase / PPPK / 7 / 8-dihydro-6-hydroxymethylpterin- ...6-hydroxymethyl-7 / 8-dihydropterin pyrophosphokinase / PPPK / 7 / 8-dihydro-6-hydroxymethylpterin-pyrophosphokinase / HPPK


Mass: 18380.008 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli (E. coli) / Strain: K12 / Gene: folK, b0142, JW0138 / Plasmid: pET14b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P26281, 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase

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Non-polymers , 5 types, 96 molecules

#2: Chemical ChemComp-APC / DIPHOSPHOMETHYLPHOSPHONIC ACID ADENOSYL ESTER / ALPHA,BETA-METHYLENEADENOSINE-5'-TRIPHOSPHATE


Mass: 505.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H18N5O12P3 / Comment: AMP-CPP, energy-carrying molecule analogue*YM
#3: Chemical ChemComp-YH5 / 2-amino-8-{[2-(4-methoxyphenyl)-2-oxoethyl]sulfanyl}-1,9-dihydro-6H-purin-6-one


Mass: 331.350 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H13N5O3S
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 90 / 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: 2.03 Å3/Da / Density % sol: 39.39 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 0.1M Tris-HCl, 0.2M calcium chloride, 25% PEG 4000, pH 8.5, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jun 5, 2013 / Details: Rosenbaum-Rock double-crystal monochromator
RadiationMonochromator: double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.696→50 Å / Num. obs: 14826 / % possible obs: 90.7 % / Observed criterion σ(I): -3 / Redundancy: 5.9 % / Rsym value: 0.065 / Net I/σ(I): 31.3
Reflection shellResolution: 1.696→1.74 Å / Redundancy: 2.7 % / Mean I/σ(I) obs: 2 / Num. unique all: 677 / Rsym value: 0.495 / % possible all: 58.4

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Processing

Software
NameVersionClassification
SERGUIdata collection
PHENIXmodel building
PHENIX(phenix.refine: 1.7.3_928)refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4M5G

4m5g


Resolution: 1.696→33.368 Å / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 22.98 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2126 743 5.02 %Random
Rwork0.1678 ---
obs0.17 14807 90.35 %-
Solvent computationShrinkage radii: 0.73 Å / VDW probe radii: 1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 60.078 Å2 / ksol: 0.4 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-8.1245 Å20 Å24.7179 Å2
2---2.7397 Å2-0 Å2
3----5.2414 Å2
Refinement stepCycle: LAST / Resolution: 1.696→33.368 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1255 0 58 90 1403
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.021375
X-RAY DIFFRACTIONf_angle_d1.4921902
X-RAY DIFFRACTIONf_dihedral_angle_d19.473517
X-RAY DIFFRACTIONf_chiral_restr0.105205
X-RAY DIFFRACTIONf_plane_restr0.006238
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.696-1.82640.31151040.23622047X-RAY DIFFRACTION66
1.8264-2.01020.21351420.18362726X-RAY DIFFRACTION89
2.0102-2.3010.20951660.16073037X-RAY DIFFRACTION98
2.301-2.89880.21161670.16413088X-RAY DIFFRACTION100
2.8988-33.3680.20571640.16253166X-RAY DIFFRACTION100
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)
11.69480.3782-0.98762.908-1.22593.7885-0.0094-0.0850.0576-0.0284-0.0028-0.074-0.04440.07960.01850.1038-0.0215-0.00910.106-0.01370.139656.91536.237340.4308
22.5283-0.8692-0.33232.6623-3.06414.31770.28350.87310.51240.0036-0.2009-0.7651-0.26670.4051-0.07920.2206-0.09140.02570.4117-0.02660.467963.867213.828741.5131
30.4777-0.9327-0.63711.83751.24510.8499-0.4988-0.50920.95060.8828-0.1188-0.3716-0.7699-0.03710.61620.4474-0.1126-0.01350.2943-0.10310.408157.067914.646633.458
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 0:158 )A0 - 158
2X-RAY DIFFRACTION2( CHAIN A AND RESID 301:301 )A301
3X-RAY DIFFRACTION3( CHAIN A AND RESID 302:302 )A302

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