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- PDB-8gkt: Human mitochondrial serine hydroxymethyltransferase (SHMT2) in co... -

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Basic information

Entry
Database: PDB / ID: 8gkt
TitleHuman mitochondrial serine hydroxymethyltransferase (SHMT2) in complex with PLP, glycine and AGF320 inhibitor
ComponentsSerine hydroxymethyltransferase, mitochondrial
KeywordsTRANSFERASE/INHIBITOR / SHMT2 / tetramer / glycine synthesis / inhibitor / TRANSFERASE / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


BRISC complex / formate biosynthetic process / L-allo-threonine aldolase activity / regulation of mitochondrial translation / glycine metabolic process / L-serine metabolic process / regulation of oxidative phosphorylation / L-serine biosynthetic process / glycine hydroxymethyltransferase / glycine hydroxymethyltransferase activity ...BRISC complex / formate biosynthetic process / L-allo-threonine aldolase activity / regulation of mitochondrial translation / glycine metabolic process / L-serine metabolic process / regulation of oxidative phosphorylation / L-serine biosynthetic process / glycine hydroxymethyltransferase / glycine hydroxymethyltransferase activity / glycine biosynthetic process from serine / Metabolism of folate and pterines / tetrahydrofolate metabolic process / response to type I interferon / protein K63-linked deubiquitination / tetrahydrofolate interconversion / regulation of aerobic respiration / amino acid binding / mitochondrial nucleoid / RHOG GTPase cycle / one-carbon metabolic process / Mitochondrial protein degradation / protein tetramerization / pyridoxal phosphate binding / microtubule cytoskeleton / protein homotetramerization / mitochondrial inner membrane / mitochondrial matrix / positive regulation of cell population proliferation / chromatin binding / mitochondrion / extracellular exosome / identical protein binding / nucleus / cytoplasm
Similarity search - Function
Serine hydroxymethyltransferase, pyridoxal phosphate binding site / Serine hydroxymethyltransferase pyridoxal-phosphate attachment site. / : / Serine hydroxymethyltransferase / Serine hydroxymethyltransferase-like domain / Serine hydroxymethyltransferase / Pyridoxal phosphate-dependent transferase, small domain / Pyridoxal phosphate-dependent transferase, major domain / Pyridoxal phosphate-dependent transferase
Similarity search - Domain/homology
Chem-PLG / Chem-Y7L / Serine hydroxymethyltransferase, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.64 Å
AuthorsKatinas, J.M. / Dann III, C.E.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 CA250469 United States
CitationJournal: Biochemistry / Year: 2024
Title: Structural Characterization of 5-Substituted Pyrrolo[3,2- d ]pyrimidine Antifolate Inhibitors in Complex with Human Serine Hydroxymethyl Transferase 2.
Authors: Katinas, J.M. / Nayeen, M.J. / Schneider, M. / Shah, K. / Fifer, A.N. / Klapper, L.M. / Sharma, A. / Thalluri, K. / Van Nieuwenhze, M.S. / Hou, Z. / Gangjee, A. / Matherly, L.H. / Dann 3rd, C.E.
History
DepositionMar 20, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 20, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Serine hydroxymethyltransferase, mitochondrial
B: Serine hydroxymethyltransferase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)110,7756
Polymers109,2122
Non-polymers1,5634
Water3,027168
1
A: Serine hydroxymethyltransferase, mitochondrial
B: Serine hydroxymethyltransferase, mitochondrial
hetero molecules

A: Serine hydroxymethyltransferase, mitochondrial
B: Serine hydroxymethyltransferase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)221,55112
Polymers218,4244
Non-polymers3,1278
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation12_564x,x-y+1,-z-1/61
Unit cell
Length a, b, c (Å)158.196, 158.196, 207.279
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number179
Space group name H-MP6522

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Components

#1: Protein Serine hydroxymethyltransferase, mitochondrial / SHMT / Glycine hydroxymethyltransferase / Serine methylase


Mass: 54605.926 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SHMT2 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P34897, glycine hydroxymethyltransferase
#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.: 2 / Source method: obtained synthetically / Formula: C10H15N2O7P
#3: Chemical ChemComp-Y7L / N-{5-[5-(2-amino-4-oxo-3,4-dihydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)pentyl]thiophene-2-carbonyl}-L-glutamic acid


Mass: 475.518 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H25N5O6S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 168 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 3.43 Å3/Da / Density % sol: 64.12 %
Crystal growTemperature: 277 K / Method: batch mode / pH: 7.5
Details: 20 mM sodium phosphate pH 7.5, 100 mM NaCl, 0.2 mM EDTA, and 0.5 mM TCEP and PLP loaded His-SHMT2 concentrated to 0.01 to 0.02 mM

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 4.2.2 / Wavelength: 1 Å
DetectorType: RDI CMOS_8M / Detector: CMOS / Date: Sep 18, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.64→48.65 Å / Num. obs: 45564 / % possible obs: 100 % / Redundancy: 12.5 % / CC1/2: 0.99 / Rmerge(I) obs: 0.345 / Rpim(I) all: 0.1 / Rrim(I) all: 0.359 / Net I/σ(I): 8.4
Reflection shellResolution: 2.64→2.73 Å / Redundancy: 9.7 % / Rmerge(I) obs: 2.576 / Mean I/σ(I) obs: 0.9 / Num. unique obs: 4369 / CC1/2: 0.389 / Rpim(I) all: 0.86 / Rrim(I) all: 2.719 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.13-2998refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.64→48.645 Å / SU ML: 0.31 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 23.86 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2467 2243 4.94 %
Rwork0.2007 --
obs0.203 45449 99.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.64→48.645 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6987 0 106 168 7261
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0047308
X-RAY DIFFRACTIONf_angle_d0.7259913
X-RAY DIFFRACTIONf_dihedral_angle_d5.8854356
X-RAY DIFFRACTIONf_chiral_restr0.0451083
X-RAY DIFFRACTIONf_plane_restr0.0041295
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.64-2.73440.33282060.30554203X-RAY DIFFRACTION99
2.7344-2.84380.30322010.27164266X-RAY DIFFRACTION100
2.8438-2.97320.27161980.24874271X-RAY DIFFRACTION100
2.9732-3.130.28312230.24114252X-RAY DIFFRACTION100
3.13-3.3260.28112200.22024275X-RAY DIFFRACTION100
3.326-3.58280.26972270.1984295X-RAY DIFFRACTION100
3.5828-3.94320.21952470.17374299X-RAY DIFFRACTION100
3.9432-4.51340.1942250.15814344X-RAY DIFFRACTION100
4.5134-5.6850.21172440.17084381X-RAY DIFFRACTION100
5.685-48.6450.25822520.19674620X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -19.4612 Å / Origin y: 65.0292 Å / Origin z: 6.3791 Å
111213212223313233
T0.2232 Å2-0.1665 Å2-0.1095 Å2-0.635 Å20.0221 Å2--0.3117 Å2
L1.07 °20.0155 °20.6929 °2-1.0324 °2-0.6604 °2--1.979 °2
S-0.1594 Å °0.0416 Å °0.1022 Å °0.2598 Å °-0.0911 Å °-0.2491 Å °-0.276 Å °0.742 Å °0.0204 Å °
Refinement TLS groupSelection details: all

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