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- PDB-4tn4: Crystal structure of ternary complex of Plasmodium vivax SHMT wit... -

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Basic information

Entry
Database: PDB / ID: 4tn4
TitleCrystal structure of ternary complex of Plasmodium vivax SHMT with glycine and a novel pyrazolopyran 33G: (4S)-6-amino-4-(5-cyano-3'-fluorobiphenyl-3-yl)-4-cyclobutyl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
ComponentsSerine hydroxymethyltransferase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / alpha and beta protein / Transferase / methyltransferase activity / Inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


purine nucleobase biosynthetic process / glycine hydroxymethyltransferase / glycine hydroxymethyltransferase activity / glycine biosynthetic process from serine / serine binding / L-serine catabolic process / tetrahydrofolate interconversion / cobalt ion binding / folic acid metabolic process / mRNA regulatory element binding translation repressor activity ...purine nucleobase biosynthetic process / glycine hydroxymethyltransferase / glycine hydroxymethyltransferase activity / glycine biosynthetic process from serine / serine binding / L-serine catabolic process / tetrahydrofolate interconversion / cobalt ion binding / folic acid metabolic process / mRNA regulatory element binding translation repressor activity / cellular response to leukemia inhibitory factor / mRNA 5'-UTR binding / pyridoxal phosphate binding / protein homotetramerization / protein homodimerization activity / zinc ion binding / nucleus / cytosol
Similarity search - Function
Serine hydroxymethyltransferase / Serine hydroxymethyltransferase-like domain / Serine hydroxymethyltransferase / Aspartate Aminotransferase, domain 1 / Aspartate Aminotransferase, domain 1 / Aspartate Aminotransferase; domain 2 / Type I PLP-dependent aspartate aminotransferase-like (Major domain) / Pyridoxal phosphate-dependent transferase, small domain / Pyridoxal phosphate-dependent transferase, major domain / Pyridoxal phosphate-dependent transferase ...Serine hydroxymethyltransferase / Serine hydroxymethyltransferase-like domain / Serine hydroxymethyltransferase / Aspartate Aminotransferase, domain 1 / Aspartate Aminotransferase, domain 1 / Aspartate Aminotransferase; domain 2 / Type I PLP-dependent aspartate aminotransferase-like (Major domain) / Pyridoxal phosphate-dependent transferase, small domain / Pyridoxal phosphate-dependent transferase, major domain / Pyridoxal phosphate-dependent transferase / Alpha-Beta Complex / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-33G / BETA-MERCAPTOETHANOL / Chem-PLG / glycine hydroxymethyltransferase
Similarity search - Component
Biological speciesPlasmodium vivax (malaria parasite P. vivax)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
Model detailsX-ray structures of ternary complex of Plasmodium vivax SHMT with glycine and a novel pyrazolopyran TH2S
AuthorsChitnumsub, P. / Jaruwat, A. / Leartsakulpanich, U. / Witschel, M.C.
Funding support Thailand, 5items
OrganizationGrant numberCountry
Synchrotron Light Research (Public Organization)Grant 2551/08 Thailand
Synchrotron Light Research (Public Organization)Grant 2-2549/LS01 Thailand
Cluster Program and Management Office, National Science and Technology development AgencyCPMO-P-13-00835 Thailand
Cluster Program and Management Office, National Science and Technology development AgencyCPMO-P-00-20029 Thailand
Cluster Program and Management Office, National Science and Technology development AgencyCPMO-DD/P-10-11274 Thailand
CitationJournal: J.Med.Chem. / Year: 2015
Title: Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT): Cocrystal Structures of Pyrazolopyrans with Potent Blood- and Liver-Stage Activities.
Authors: Witschel, M.C. / Rottmann, M. / Schwab, A. / Leartsakulpanich, U. / Chitnumsub, P. / Seet, M. / Tonazzi, S. / Schwertz, G. / Stelzer, F. / Mietzner, T. / McNamara, C. / Thater, F. / ...Authors: Witschel, M.C. / Rottmann, M. / Schwab, A. / Leartsakulpanich, U. / Chitnumsub, P. / Seet, M. / Tonazzi, S. / Schwertz, G. / Stelzer, F. / Mietzner, T. / McNamara, C. / Thater, F. / Freymond, C. / Jaruwat, A. / Pinthong, C. / Riangrungroj, P. / Oufir, M. / Hamburger, M. / Maser, P. / Sanz-Alonso, L.M. / Charman, S. / Wittlin, S. / Yuthavong, Y. / Chaiyen, P. / Diederich, F.
History
DepositionJun 3, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 25, 2015Provider: repository / Type: Initial release
Revision 1.1Apr 1, 2015Group: Database references
Revision 1.2Apr 22, 2015Group: Database references
Revision 1.3Nov 22, 2017Group: Database references / Derived calculations ...Database references / Derived calculations / Refinement description / Source and taxonomy
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_struct_oper_list / software
Item: _citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_oper_list.symmetry_operation
Revision 1.4Sep 27, 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_special_symmetry
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Serine hydroxymethyltransferase
B: Serine hydroxymethyltransferase
C: Serine hydroxymethyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)150,24814
Polymers147,7473
Non-polymers2,50011
Water8,683482
1
A: Serine hydroxymethyltransferase
B: Serine hydroxymethyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,1539
Polymers98,4982
Non-polymers1,6557
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9980 Å2
ΔGint-52 kcal/mol
Surface area29980 Å2
MethodPISA
2
C: Serine hydroxymethyltransferase
hetero molecules

C: Serine hydroxymethyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,18910
Polymers98,4982
Non-polymers1,6918
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_655-x+1,y,-z1
Buried area10200 Å2
ΔGint-83 kcal/mol
Surface area29840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)100.412, 57.989, 236.955
Angle α, β, γ (deg.)90.000, 89.990, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11C-504-

CL

DetailsThe biological unit is the same as asymmetric unit

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Components

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Protein , 1 types, 3 molecules ABC

#1: Protein Serine hydroxymethyltransferase


Mass: 49249.160 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Details: Plasmodium vivax SHMT with PLP-glycine Schiff base and a novel pyrazolopyran TH2S
Source: (gene. exp.) Plasmodium vivax (malaria parasite P. vivax)
Strain: Salvador I / Gene: PVX_100730 / Plasmid: pET17b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: A5K8L9

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Non-polymers , 5 types, 493 molecules

#2: Chemical ChemComp-PLG / N-GLYCINE-[3-HYDROXY-2-METHYL-5-PHOSPHONOOXYMETHYL-PYRIDIN-4-YL-METHANE] / N-PYRIDOXYL-GLYCINE-5-MONOPHOSPHATE


Mass: 306.209 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C10H15N2O7P
#3: Chemical ChemComp-BME / BETA-MERCAPTOETHANOL


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS
#4: Chemical ChemComp-33G / (4S)-6-amino-4-(5-cyano-3'-fluorobiphenyl-3-yl)-4-cyclobutyl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile


Mass: 425.458 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C25H20FN5O
#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.: 482 / 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: 2.33 Å3/Da / Density % sol: 47.31 %
Crystal growTemperature: 297 K / Method: vapor diffusion / pH: 8.5 / Details: PEG4000, 0.06-0.12 M NaCl, 0.1 M Tris-HCl pH 8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSRRC / Beamline: BL13B1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 29, 2013 / Details: Rh Coated mirrors
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→30 Å / Num. obs: 64394 / % possible obs: 92.5 % / Redundancy: 2.4 % / Rmerge(I) obs: 0.015 / Χ2: 0.596 / Net I/av σ(I): 42.485 / Net I/σ(I): 44.9 / Num. measured all: 151739
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.2-2.281.90.06558020.73883.9
2.28-2.3720.0560130.62987
2.37-2.4820.04161180.65589.4
2.48-2.612.10.03663280.73590.4
2.61-2.772.20.02665880.69194.8
2.77-2.992.30.0266660.62196.7
2.99-3.292.60.01566990.48296.6
3.29-3.762.80.01367120.4896.1
3.76-4.732.80.01667390.76596
4.73-302.80.01167290.36793.6

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Processing

Software
NameVersionClassification
Blu-Icedata collection
HKL-2000data scaling
REFMAC5.6.0117refinement
PDB_EXTRACT3.14data extraction
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4OYT

4oyt


Resolution: 2.2→30 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.882 / SU B: 8.51 / SU ML: 0.212 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.456 / ESU R Free: 0.292 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2855 6489 10.1 %RANDOM
Rwork0.2174 57887 --
obs0.2242 64376 92.35 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 82.45 Å2 / Biso mean: 31.512 Å2 / Biso min: 9.11 Å2
Baniso -1Baniso -2Baniso -3
1-0.22 Å20 Å20 Å2
2---0.18 Å20 Å2
3----0.03 Å2
Refinement stepCycle: final / Resolution: 2.2→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10374 0 170 482 11026
Biso mean--45.49 31.38 -
Num. residues----1326
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0210755
X-RAY DIFFRACTIONr_angle_refined_deg1.5241.97614541
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7951329
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.22325.247486
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.808151914
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.4371548
X-RAY DIFFRACTIONr_chiral_restr0.0880.21611
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0218097
LS refinement shellResolution: 2.201→2.258 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.349 416 -
Rwork0.278 3655 -
all-4071 -
obs--82.18 %

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