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- PDB-8t4p: Human mitochondrial serine hydroxymethyltransferase (SHMT2) in co... -

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Basic information

Entry
Database: PDB / ID: 8t4p
TitleHuman mitochondrial serine hydroxymethyltransferase (SHMT2) in complex with PLP, glycine and di-glutamate AGF347 inhibitor
ComponentsSerine hydroxymethyltransferase, mitochondrial
KeywordsTRANSFERASE / Mitochondrial / one-carbon metabolism / polyglutamate / inhibitor / complex / serine and glycine metabolism
Function / homology
Function and homology information


BRISC complex / 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 ...BRISC complex / 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 / Mitochondrial protein degradation / one-carbon metabolic process / 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 / : / Serine hydroxymethyltransferase, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.801 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
DepositionJun 9, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 21, 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)110,4875
Polymers109,2722
Non-polymers1,2153
Water45025
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)220,97410
Polymers218,5444
Non-polymers2,4306
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)159.288, 159.288, 208.649
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: 54635.949 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: First 31 residues are part of the hexa-His tag and TEV protease site. Any additional residue to A mutations are due to lack of density in the side chain. Any missing residues are due to lack ...Details: First 31 residues are part of the hexa-His tag and TEV protease site. Any additional residue to A mutations are due to lack of density in the side chain. Any missing residues are due to lack of density in the backbone or side chain and inability to model a specific conformation.
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-Y5Z / N-{4-[4-(2-amino-4-oxo-3,4-dihydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl]-2-fluorobenzoyl}-L-gamma-glutamyl-L-glutamic acid


Mass: 602.568 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C27H31FN6O9 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 25 / 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: 3.5 Å3/Da / Density % sol: 64.84 %
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: 293 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 4.2.2 / Wavelength: 1 Å
DetectorType: RDI CMOS_8M / Detector: CMOS / Date: Nov 10, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.8→48.791 Å / Num. obs: 203843 / % possible obs: 92 % / Redundancy: 5.7 % / CC1/2: 0.98 / Net I/σ(I): 9.4
Reflection shellResolution: 2.8→2.93 Å / Rmerge(I) obs: 0.702 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 26923 / CC1/2: 0.755 / Rpim(I) all: 0.318 / Rrim(I) all: 0.772

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.801→48.791 Å / SU ML: 0.42 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 30.48 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3002 1756 4.91 %
Rwork0.2583 --
obs0.2604 35794 91.75 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.801→48.791 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6861 0 83 25 6969
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0037092
X-RAY DIFFRACTIONf_angle_d0.6079620
X-RAY DIFFRACTIONf_dihedral_angle_d4.6875066
X-RAY DIFFRACTIONf_chiral_restr0.041060
X-RAY DIFFRACTIONf_plane_restr0.0031272
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8015-2.90160.39381760.31753645X-RAY DIFFRACTION100
2.9016-3.01780.30212000.27663616X-RAY DIFFRACTION100
3.0178-3.15510.31992720.26993649X-RAY DIFFRACTION100
3.1551-3.32140.35361920.29223659X-RAY DIFFRACTION100
3.3214-3.52940.35081110.33632459X-RAY DIFFRACTION67
3.5294-3.80190.36411380.32332698X-RAY DIFFRACTION73
3.8019-4.18430.32591510.27332862X-RAY DIFFRACTION78
4.1843-4.78930.26942180.21163691X-RAY DIFFRACTION100
4.7893-6.03220.26271750.22283798X-RAY DIFFRACTION100
6.0322-48.7910.25012230.22593961X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -19.9072 Å / Origin y: 65.6476 Å / Origin z: 6.8826 Å
111213212223313233
T0.34 Å2-0.1642 Å2-0.1042 Å2-0.6688 Å20.0699 Å2--0.1887 Å2
L0.895 °2-0.0815 °20.6891 °2-0.8967 °2-0.6115 °2--1.7302 °2
S-0.151 Å °0.0244 Å °0.1385 Å °0.2383 Å °-0.1555 Å °-0.2637 Å °-0.297 Å °0.5057 Å °0.0289 Å °
Refinement TLS groupSelection details: all

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