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- PDB-2j0f: Structural basis for non-competitive product inhibition in human ... -

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Basic information

Entry
Database: PDB / ID: 2j0f
TitleStructural basis for non-competitive product inhibition in human thymidine phosphorylase: implication for drug design
ComponentsTHYMIDINE PHOSPHORYLASE
KeywordsTRANSFERASE / HTP / CHEMOTAXIS / POLYMORPHISM / DISEASE MUTATION / GLYCOSYLTRANSFERASE / ANGIOGENESIS / GROWTH FACTOR / DIFFERENTIATION / DEVELOPMENTAL PROTEIN / HUMAN THYMIDINE PHOSPHORYLASE
Function / homology
Function and homology information


thymidine phosphorylase / regulation of gastric motility / dTMP catabolic process / pyrimidine nucleoside metabolic process / regulation of transmission of nerve impulse / thymidine phosphorylase activity / pyrimidine nucleobase metabolic process / 1,4-alpha-oligoglucan phosphorylase activity / Pyrimidine catabolism / Pyrimidine salvage ...thymidine phosphorylase / regulation of gastric motility / dTMP catabolic process / pyrimidine nucleoside metabolic process / regulation of transmission of nerve impulse / thymidine phosphorylase activity / pyrimidine nucleobase metabolic process / 1,4-alpha-oligoglucan phosphorylase activity / Pyrimidine catabolism / Pyrimidine salvage / : / regulation of myelination / growth factor activity / chemotaxis / angiogenesis / cell differentiation / protein homodimerization activity / cytosol
Similarity search - Function
Pyrimidine-nucleoside phosphorylase, bacterial/eukaryotic / Pyrimidine nucleoside phosphorylase-like, C-terminal domain / Thymidine/pyrimidine-nucleoside phosphorylase / Pyrimidine nucleoside phosphorylase, C-terminal / Pyrimidine-nucleoside phosphorylase, conserved site / Pyrimidine nucleoside phosphorylase-like, C-terminal domain superfamily / Pyrimidine nucleoside phosphorylase C-terminal domain / Thymidine and pyrimidine-nucleoside phosphorylases signature. / Pyrimidine nucleoside phosphorylase C-terminal domain / Transferase, Pyrimidine Nucleoside Phosphorylase; Chain C ...Pyrimidine-nucleoside phosphorylase, bacterial/eukaryotic / Pyrimidine nucleoside phosphorylase-like, C-terminal domain / Thymidine/pyrimidine-nucleoside phosphorylase / Pyrimidine nucleoside phosphorylase, C-terminal / Pyrimidine-nucleoside phosphorylase, conserved site / Pyrimidine nucleoside phosphorylase-like, C-terminal domain superfamily / Pyrimidine nucleoside phosphorylase C-terminal domain / Thymidine and pyrimidine-nucleoside phosphorylases signature. / Pyrimidine nucleoside phosphorylase C-terminal domain / Transferase, Pyrimidine Nucleoside Phosphorylase; Chain C / Transferase, Pyrimidine Nucleoside Phosphorylase; Chain A, domain 3 / Pyrimidine Nucleoside Phosphorylase; Chain A, domain 2 / Nucleoside phosphorylase/phosphoribosyltransferase catalytic domain / Glycosyl transferase family 3, N-terminal domain / Glycosyl transferase family 3, N-terminal domain superfamily / Glycosyl transferase family, helical bundle domain / Glycosyl transferase, family 3 / Glycosyl transferase family, a/b domain / Nucleoside phosphorylase/phosphoribosyltransferase catalytic domain superfamily / Aldehyde Oxidoreductase; domain 3 / Alpha-Beta Complex / Up-down Bundle / 3-Layer(aba) Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
THYMINE / Thymidine phosphorylase
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.31 Å
AuthorsEl Omari, K. / Bronckaers, A. / Liekens, S. / Perez-Perez, M.J. / Balzarini, J. / Stammers, D.K.
CitationJournal: Biochem.J. / Year: 2006
Title: Structural Basis for Non-Competitive Product Inhibition in Human Thymidine Phosphorylase: Implications for Drug Design.
Authors: El Omari, K. / Bronckaers, A. / Liekens, S. / Perez-Perez, M. / Balzarini, J. / Stammers, D.K.
History
DepositionAug 2, 2006Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 11, 2006Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: THYMIDINE PHOSPHORYLASE
B: THYMIDINE PHOSPHORYLASE
C: THYMIDINE PHOSPHORYLASE
D: THYMIDINE PHOSPHORYLASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)200,5007
Polymers200,1224
Non-polymers3783
Water8,107450
1
A: THYMIDINE PHOSPHORYLASE
C: THYMIDINE PHOSPHORYLASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,3134
Polymers100,0612
Non-polymers2522
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
2
B: THYMIDINE PHOSPHORYLASE
D: THYMIDINE PHOSPHORYLASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,1873
Polymers100,0612
Non-polymers1261
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)103.078, 76.087, 99.575
Angle α, β, γ (deg.)90.00, 98.61, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
31C
41D

NCS domain segments:

Ens-ID: 1 / Refine code: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11GLUGLUVALVALAA38 - 23438 - 234
21GLUGLUVALVALBB38 - 23438 - 234
31GLUGLUVALVALCC38 - 23438 - 234
41GLUGLUVALVALDD38 - 23438 - 234
12ALAALAALAALAAA248 - 269248 - 269
22ALAALAALAALABB248 - 269248 - 269
32ALAALAALAALACC248 - 269248 - 269
42ALAALAALAALADD248 - 269248 - 269
13LEULEUARGARGAA277 - 442277 - 442
23LEULEUARGARGBB277 - 442277 - 442
33LEULEUARGARGCC277 - 442277 - 442
43LEULEUARGARGDD277 - 442277 - 442
14PROPROLEULEUAA450 - 471450 - 471
24PROPROLEULEUBB450 - 471450 - 471
34PROPROLEULEUCC450 - 471450 - 471
44PROPROLEULEUDD450 - 471450 - 471

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Components

#1: Protein
THYMIDINE PHOSPHORYLASE / TDRPASE / TP / PLATELET-DERIVED ENDOTHELIAL CELL GROWTH FACTOR / GLIOSTATIN / PD-ECGF


Mass: 50030.379 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P19971, thymidine phosphorylase
#2: Chemical ChemComp-TDR / THYMINE


Mass: 126.113 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C5H6N2O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 450 / 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: 2.04 Å3/Da / Density % sol: 39.26 %
Crystal growpH: 7 / Details: 20% GLYCEROL, 20% PEG3350, pH 7.00

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: MAR345 / Wavelength: 1.5418
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Oct 15, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.3→30 Å / Num. obs: 63091 / % possible obs: 99.3 % / Observed criterion σ(I): 2 / Redundancy: 8.6 % / Rmerge(I) obs: 0.12 / Net I/σ(I): 18.2
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 8 % / % possible all: 99

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1UOU

1uou


Resolution: 2.31→102.06 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.895 / SU B: 20.744 / SU ML: 0.252 / Cross valid method: THROUGHOUT / ESU R: 0.71 / ESU R Free: 0.314 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. PSEUDO TRANSLATION DETECTED. MOLECULE D DISORDERED.
RfactorNum. reflection% reflectionSelection details
Rfree0.287 3368 5.1 %RANDOM
Rwork0.246 ---
obs0.248 63091 99.3 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 12.84 Å2
Baniso -1Baniso -2Baniso -3
1--2.52 Å20 Å20.3 Å2
2---1.2 Å20 Å2
3---3.81 Å2
Refinement stepCycle: LAST / Resolution: 2.31→102.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13036 0 27 450 13513
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.02213247
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.2472.00117968
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.51851780
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.02523.492504
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.279152216
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.69115128
X-RAY DIFFRACTIONr_chiral_restr0.0760.22108
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.029935
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2060.26366
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.2920.29087
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1730.2562
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.3420.2216
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.3620.232
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.8291.59072
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.461213948
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.88834615
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it5.4044.54020
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 2973 / Refine-ID: X-RAY DIFFRACTION

Dom-IDAuth asym-IDTypeRms dev position (Å)Weight position
1Atight positional0.050.05
2Btight positional0.040.05
3Ctight positional0.050.05
4Dtight positional0.030.05
1Atight thermal0.090.5
2Btight thermal0.090.5
3Ctight thermal0.090.5
4Dtight thermal0.070.5
LS refinement shellResolution: 2.31→2.37 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.394 237
Rwork0.317 4289

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