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- PDB-4kpw: Crystal structure of His-tagged human thymidylate synthase R175A ... -

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Basic information

Entry
Database: PDB / ID: 4kpw
TitleCrystal structure of His-tagged human thymidylate synthase R175A mutant
ComponentsThymidylate synthase
KeywordsTRANSFERASE / interface hot spot / METHYLTRANSFERASE / NUCLEOTIDE BIOSYNTHESIS
Function / homology
Function and homology information


uracil metabolic process / response to organophosphorus / intestinal epithelial cell maturation / response to folic acid / Interconversion of nucleotide di- and triphosphates / response to vitamin A / thymidylate synthase / sequence-specific mRNA binding / cartilage development / tetrahydrofolate interconversion ...uracil metabolic process / response to organophosphorus / intestinal epithelial cell maturation / response to folic acid / Interconversion of nucleotide di- and triphosphates / response to vitamin A / thymidylate synthase / sequence-specific mRNA binding / cartilage development / tetrahydrofolate interconversion / thymidylate synthase activity / folic acid binding / dTMP biosynthetic process / dTTP biosynthetic process / DNA biosynthetic process / G1/S-Specific Transcription / developmental growth / dihydrofolate reductase activity / response to glucocorticoid / mRNA regulatory element binding translation repressor activity / response to progesterone / response to cytokine / liver regeneration / response to toxic substance / circadian rhythm / methylation / response to ethanol / mitochondrial inner membrane / negative regulation of translation / mitochondrial matrix / response to xenobiotic stimulus / protein homodimerization activity / mitochondrion / nucleus / cytosol / cytoplasm
Similarity search - Function
Thymidylate Synthase; Chain A / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase/dCMP hydroxymethylase / Thymidylate synthase, active site / Thymidylate synthase active site. / Thymidylate synthase / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase/dCMP hydroxymethylase superfamily / Thymidylate synthase / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Thymidylate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.03 Å
AuthorsPozzi, C. / Mangani, S.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Hotspots in an obligate homodimeric anticancer target. Structural and functional effects of interfacial mutations in human thymidylate synthase.
Authors: Salo-Ahen, O.M. / Tochowicz, A. / Pozzi, C. / Cardinale, D. / Ferrari, S. / Boum, Y. / Mangani, S. / Stroud, R.M. / Saxena, P. / Myllykallio, H. / Costi, M.P. / Ponterini, G. / Wade, R.C.
History
DepositionMay 14, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 14, 2014Provider: repository / Type: Initial release
Revision 1.1May 6, 2015Group: Database references
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software
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 / 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 / _struct_conn.pdbx_leaving_atom_flag / _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: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,8317
Polymers37,3571
Non-polymers4746
Water2,954164
1
A: Thymidylate synthase
hetero molecules

A: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,66214
Polymers74,7142
Non-polymers94912
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_554x-y,-y,-z-1/31
Buried area6150 Å2
ΔGint-75 kcal/mol
Surface area22400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)96.320, 96.320, 82.690
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121

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Components

#1: Protein Thymidylate synthase / / TS / TSase


Mass: 37356.781 Da / Num. of mol.: 1 / Mutation: R175A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TYMS, TS, OK/SW-cl.29 / Production host: Escherichia coli (E. coli) / References: UniProt: P04818, thymidylate synthase
#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 164 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.96 Å3/Da / Density % sol: 58.5 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 8.8
Details: 30 % saturated ammonium sulfate, 20 mM BETA-MERCAPTOETHANOL, and 0.1 M Tris-HCl, pH 8.8, VAPOR DIFFUSION, HANGING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.8736 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Apr 8, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8736 Å / Relative weight: 1
ReflectionResolution: 2.03→37.24 Å / Num. all: 29034 / Num. obs: 29020 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 1.9 / Redundancy: 6.2 % / Biso Wilson estimate: 31.1 Å2 / Rmerge(I) obs: 0.065 / Net I/σ(I): 16.1
Reflection shellResolution: 2.03→2.14 Å / Redundancy: 6.3 % / Rmerge(I) obs: 0.396 / Mean I/σ(I) obs: 4.6 / Num. unique all: 4215 / % possible all: 100

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Processing

Software
NameVersionClassification
MOLREPphasing
PHENIX(phenix.refine: 1.8.2_1309)refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 3N5G

3n5g


Resolution: 2.03→37.239 Å / SU ML: 0.21 / σ(F): 0 / Phase error: 18.13 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2049 1475 5.08 %Random
Rwork0.161 ---
all0.1632 29020 --
obs0.1632 29020 99.9 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.03→37.239 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2139 0 27 164 2330
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072215
X-RAY DIFFRACTIONf_angle_d1.0812989
X-RAY DIFFRACTIONf_dihedral_angle_d14.421821
X-RAY DIFFRACTIONf_chiral_restr0.078314
X-RAY DIFFRACTIONf_plane_restr0.005383
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.03-2.09560.29741300.2292502X-RAY DIFFRACTION100
2.0956-2.17040.23331640.19492417X-RAY DIFFRACTION100
2.1704-2.25730.22121270.18242494X-RAY DIFFRACTION100
2.2573-2.36010.25151220.17832497X-RAY DIFFRACTION100
2.3601-2.48450.21711580.16712454X-RAY DIFFRACTION100
2.4845-2.64010.18171230.16422484X-RAY DIFFRACTION100
2.6401-2.84380.20081300.16242493X-RAY DIFFRACTION100
2.8438-3.12990.20831310.17212513X-RAY DIFFRACTION100
3.1299-3.58250.20771310.16292517X-RAY DIFFRACTION100
3.5825-4.51230.18661410.13562532X-RAY DIFFRACTION100
4.5123-37.24520.1941180.15642642X-RAY DIFFRACTION99
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)
16.1964-3.192-2.72052.69191.60199.29480.0250.6381-0.5422-0.43250.0257-0.09540.7897-0.0073-0.02950.4924-0.1237-0.0720.1851-0.0390.409439.0712-17.6892-19.3018
22.60670.49870.21663.38670.38081.84390.2804-0.4895-0.30630.6784-0.0531-0.13930.1238-0.0584-0.19860.3993-0.0803-0.04030.17790.05550.238342.6251-8.71141.9468
39.7893-3.8279-0.9652.53073.14937.5667-0.0706-1.5528-2.5460.4484-0.06961.08041.57230.39940.21911.4012-0.0002-0.09930.97210.29921.297358.5572-17.90996.8536
43.3763-0.09080.34673.1957-4.85467.44950.36660.3713-0.7521-1.3385-0.4182-1.111.47521.39840.14920.72470.1671-0.06670.69090.04380.843364.88-9.8934-2.3212
54.3142-0.8918-0.38024.20881.97335.03760.4699-0.054-0.00070.4974-0.2125-1.00750.26010.6261-0.22130.4207-0.0885-0.11450.30320.03280.335460.3406-0.517-3.7731
63.8945-4.9988-4.91459.19916.28229.1810.1058-0.3757-0.09850.1270.0365-0.0817-0.14350.417-0.01530.3686-0.0357-0.02070.1804-0.04450.222149.23212.7748-5.5364
72.0450.6395-0.21223.3465-0.11861.55290.2388-0.321-0.20150.3717-0.13820.01030.0623-0.0952-0.0880.3615-0.0657-0.00150.18290.06480.194642.06-7.793-0.314
84.63971.17710.7593.1687-0.86812.62320.2521-0.645-0.39410.5893-0.16610.0563-0.14610.0249-0.10170.5241-0.14830.04340.33420.14660.320139.5532-15.2667.5993
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( chain A and resseq 38:58 )A38 - 58
2X-RAY DIFFRACTION2( chain A and resseq 59:93 )A59 - 93
3X-RAY DIFFRACTION3( chain A and resseq 94:107 )A94 - 107
4X-RAY DIFFRACTION4( chain A and resseq 108:148 )A108 - 148
5X-RAY DIFFRACTION5( chain A and resseq 149:191 )A149 - 191
6X-RAY DIFFRACTION6( chain A and resseq 192:210 )A192 - 210
7X-RAY DIFFRACTION7( chain A and resseq 211:291 )A211 - 291
8X-RAY DIFFRACTION8( chain A and resseq 292:323 )A292 - 323

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