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- PDB-2aaz: Cryptococcus neoformans thymidylate synthase complexed with subst... -

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Basic information

Entry
Database: PDB / ID: 2aaz
TitleCryptococcus neoformans thymidylate synthase complexed with substrate and an antifolate
ComponentsThymidylate synthase
KeywordsTRANSFERASE / Methyl transferase / Nucleotide biosynthesis
Function / homology
Function and homology information


thymidylate synthase / thymidylate synthase activity / dTMP biosynthetic process / dTTP biosynthetic process / methylation / mitochondrion / cytosol
Similarity search - Function
Thymidylate Synthase; Chain A / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase, active site / Thymidylate synthase active site. / Thymidylate synthase / Thymidylate synthase/dCMP hydroxymethylase / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase/dCMP hydroxymethylase superfamily / Thymidylate synthase / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
10-PROPARGYL-5,8-DIDEAZAFOLIC ACID / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / Thymidylate synthase / Thymidylate synthase
Similarity search - Component
Biological speciesFilobasidiella neoformans (Cryptococcus neoformans serotype A)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.08 Å
AuthorsFiner-Moore, J.S. / Anderson, A.C. / O'Neil, R.H. / Costi, M.P. / Ferrari, S. / Krucinski, J. / Stroud, R.M.
Citation
Journal: Acta Crystallogr.,Sect.D / Year: 2005
Title: The structure of Cryptococcus neoformans thymidylate synthase suggests strategies for using target dynamics for species-specific inhibition.
Authors: Finer-Moore, J.S. / Anderson, A.C. / O'Neil, R.H. / Costi, M.P. / Ferrari, S. / Krucinski, J. / Stroud, R.M.
#1: Journal: J.Med.Chem. / Year: 1999
Title: Phthalein derivatives as a new tool for selectivity in thymidylate synthase inhibition
Authors: Costi, P.M. / Rinaldi, M. / Tondi, D. / Pecorari, P. / Barlocco, D. / Ghelli, S. / Stroud, R.M. / Santi, D.V. / Stout, T.J. / Musiu, C. / Marangiu, E.M. / Pani, A. / Congiu, D. / Loi, G.A. / La Colla, P.
#2: Journal: Biochemistry / Year: 1999
Title: Structure-based design of inhibitors specific for bacterial thymidylate synthase
Authors: Stout, T.J. / Tondi, D. / Rinaldi, M. / Barlocco, D. / Pecorari, P. / Santi, D.V. / Kuntz, I.D. / Stroud, R.M. / Shoichet, B.K. / Costi, M.P.
History
DepositionJul 14, 2005Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 6, 2005Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Sep 9, 2015Group: Version format compliance
Revision 1.4Feb 14, 2018Group: Experimental preparation / Category: exptl_crystal_grow
Item: _exptl_crystal_grow.pdbx_details / _exptl_crystal_grow.temp
Revision 1.5Oct 9, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_conn / 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_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

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Assembly

Deposited unit
A: Thymidylate synthase
B: Thymidylate synthase
C: Thymidylate synthase
D: Thymidylate synthase
E: Thymidylate synthase
F: Thymidylate synthase
G: Thymidylate synthase
H: Thymidylate synthase
I: Thymidylate synthase
J: Thymidylate synthase
K: Thymidylate synthase
L: Thymidylate synthase
M: Thymidylate synthase
N: Thymidylate synthase
O: Thymidylate synthase
P: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)583,34240
Polymers574,59216
Non-polymers8,75124
Water21,8341212
1
A: Thymidylate synthase
B: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,3956
Polymers71,8242
Non-polymers1,5714
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Thymidylate synthase
D: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,3956
Polymers71,8242
Non-polymers1,5714
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
E: Thymidylate synthase
F: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,3956
Polymers71,8242
Non-polymers1,5714
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
G: Thymidylate synthase
H: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,3956
Polymers71,8242
Non-polymers1,5714
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
I: Thymidylate synthase
J: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,4404
Polymers71,8242
Non-polymers6162
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
6
K: Thymidylate synthase
L: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,4404
Polymers71,8242
Non-polymers6162
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
7
M: Thymidylate synthase
N: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,4404
Polymers71,8242
Non-polymers6162
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
8
O: Thymidylate synthase
P: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,4404
Polymers71,8242
Non-polymers6162
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)179.400, 179.500, 209.100
Angle α, β, γ (deg.)90.00, 89.80, 90.00
Int Tables number5
Space group name H-MC121
Number of models4
Components on special symmetry positions
IDModelComponents
13O-135-

GLY

DetailsThe biological assembly is a dimer. There are 8 dimers in the asymmetric unit and four of these dimers are 4-fold statistically disordered. Pairs of chains that constitute the four fully-occupied biological dimers are (A,B), (C,D), (E,F) and (G,H). Dimers that are in four 1/4-occupied packing arrangements in the cell are chains (I,J), (K,L), (M,N) and (O,P)

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Components

#1: Protein
Thymidylate synthase / TS / TSase


Mass: 35911.977 Da / Num. of mol.: 16
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Filobasidiella neoformans (Cryptococcus neoformans serotype A)
Gene: TMP1 / Plasmid: pET CNTS / Species (production host): Escherichia coli / Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL21
References: UniProt: P45351, UniProt: P0CS12*PLUS, thymidylate synthase
#2: Chemical
ChemComp-UMP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / DUMP


Mass: 308.182 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: C9H13N2O8P
#3: Chemical
ChemComp-CB3 / 10-PROPARGYL-5,8-DIDEAZAFOLIC ACID


Mass: 477.469 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C24H23N5O6
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1212 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.93 Å3/Da / Density % sol: 57.99 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.4
Details: 0.107 mM protein, dUMP,CB3, DTT, PEG4000/PEG6000, Tris, Na acetate/K acetate, pH 8.4, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 103 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-1 / Wavelength: 1 Å
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: May 19, 2000 / Details: monochrometer
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.07→99 Å / Num. all: 389001 / Num. obs: 389001 / % possible obs: 97 % / Observed criterion σ(F): -3 / Observed criterion σ(I): -3 / Redundancy: 1.85 % / Biso Wilson estimate: 23.2 Å2 / Rmerge(I) obs: 0.1 / Net I/σ(I): 7.4
Reflection shellResolution: 2.07→2.14 Å / Rmerge(I) obs: 0.344 / Mean I/σ(I) obs: 1.7 / % possible all: 97.9

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Processing

Software
NameVersionClassification
CNS1.1refinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.08→49.91 Å / Rfactor Rfree error: 0.002 / Data cutoff high absF: 5580798.34 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
Details: Tight NCS restraints used throughout refinement. Structures of all monomers in the asymmetric unit restrained to be equivalent except for the following C. neoformans thymidylate synthase ...Details: Tight NCS restraints used throughout refinement. Structures of all monomers in the asymmetric unit restrained to be equivalent except for the following C. neoformans thymidylate synthase inserts: residues 13-16, 107-108 200-202. The following residues not present in the model: 1-12 for chains A-H and side chain of K107 in chains A and C, residues 1-15 and 200-202 in chains I-P.
RfactorNum. reflection% reflectionSelection details
Rfree0.305 34851 10 %RANDOM
Rwork0.29 ---
obs0.29 348326 88.1 %-
all-383515 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 49.4499 Å2 / ksol: 0.20613 e/Å3
Displacement parametersBiso mean: 28.5 Å2
Baniso -1Baniso -2Baniso -3
1-7.3 Å20 Å2-0.95 Å2
2---10.6 Å20 Å2
3----1.31 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.4 Å0.37 Å
Luzzati d res low-5 Å
Luzzati sigma a0.26 Å0.23 Å
Refinement stepCycle: LAST / Resolution: 2.08→49.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms38536 0 600 1212 40348
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.011
X-RAY DIFFRACTIONc_angle_deg1.6
X-RAY DIFFRACTIONc_dihedral_angle_d23.2
X-RAY DIFFRACTIONc_improper_angle_d1.51
X-RAY DIFFRACTIONc_mcbond_it1.71.5
X-RAY DIFFRACTIONc_mcangle_it2.272
X-RAY DIFFRACTIONc_scbond_it2.762
X-RAY DIFFRACTIONc_scangle_it3.552.5
Refine LS restraints NCSNCS model details: CONSTR
LS refinement shellResolution: 2.08→2.21 Å / Rfactor Rfree error: 0.005 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.348 5778 10.2 %
Rwork0.332 50830 -
obs--86.3 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water_rep.paramwater.top
X-RAY DIFFRACTION3paramed.ligump_po4.top
X-RAY DIFFRACTION4topo.cb3

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