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- PDB-8gkz: Human mitochondrial serine hydroxymethyltransferase (SHMT2) Y105F... -

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Basic information

Entry
Database: PDB / ID: 8gkz
TitleHuman mitochondrial serine hydroxymethyltransferase (SHMT2) Y105F in complex with PLP, glycine and AGF362 inhibitor
ComponentsSerine hydroxymethyltransferase, mitochondrial
KeywordsTRANSFERASE/INHIBITOR / SHMT2 mutant / tetramer / glycine synthesis / inhibitor / TRANSFERASE / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


BRISC complex / L-allo-threonine aldolase activity / regulation of mitochondrial translation / L-serine metabolic process / glycine metabolic process / L-serine biosynthetic process / glycine hydroxymethyltransferase / glycine hydroxymethyltransferase activity / glycine biosynthetic process from serine / serine binding ...BRISC complex / L-allo-threonine aldolase activity / regulation of mitochondrial translation / L-serine metabolic process / glycine metabolic process / L-serine biosynthetic process / glycine hydroxymethyltransferase / glycine hydroxymethyltransferase activity / glycine biosynthetic process from serine / serine binding / Metabolism of folate and pterines / L-serine catabolic process / regulation of oxidative phosphorylation / tetrahydrofolate metabolic process / response to type I interferon / protein K63-linked deubiquitination / tetrahydrofolate interconversion / regulation of aerobic respiration / cobalt ion binding / mitochondrial nucleoid / RHOG GTPase cycle / folic acid metabolic process / Mitochondrial protein degradation / protein tetramerization / microtubule cytoskeleton / pyridoxal phosphate binding / one-carbon metabolic process / protein homotetramerization / mitochondrial inner membrane / mitochondrial matrix / chromatin binding / positive regulation of cell population proliferation / mitochondrion / zinc ion binding / 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
GLYCINE / PYRIDOXAL-5'-PHOSPHATE / Chem-Y72 / Serine hydroxymethyltransferase, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.75 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)110,3047
Polymers109,1802
Non-polymers1,1245
Water36020
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)220,60814
Polymers218,3604
Non-polymers2,24810
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation12_564x,x-y+1,-z-1/61
Buried area24240 Å2
ΔGint-92 kcal/mol
Surface area58800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)158.250, 158.250, 207.990
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: 54589.926 Da / Num. of mol.: 2 / Mutation: Y105F
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-GLY / GLYCINE


Type: peptide linking / Mass: 75.067 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H5NO2
#3: Chemical ChemComp-PLP / PYRIDOXAL-5'-PHOSPHATE / VITAMIN B6 Phosphate


Mass: 247.142 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H10NO6P
#4: Chemical ChemComp-Y72 / N-{4-[4-(2-amino-4-oxo-3,4-dihydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl]-3-fluorothiophene-2-carbonyl}-L-glutamic acid


Mass: 479.482 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H22FN5O6S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 20 / 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: 64.13 %
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: Jun 23, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.61→48.74 Å / Num. obs: 46865 / % possible obs: 99.1 % / Redundancy: 9.7 % / CC1/2: 0.95 / Rmerge(I) obs: 0.177 / Rpim(I) all: 0.062 / Rrim(I) all: 0.189 / Net I/σ(I): 13.7
Reflection shellResolution: 2.61→2.7 Å / Rmerge(I) obs: 3.337 / Mean I/σ(I) obs: 0.8 / Num. unique obs: 4154 / CC1/2: 0.47 / Rpim(I) all: 2.006 / Rrim(I) all: 3.967

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Processing

Software
NameVersionClassification
PHENIX1.13-2998refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.75→48.736 Å / SU ML: 0.35 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 26.44 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.267 2045 5.09 %
Rwork0.2147 --
obs0.2173 40171 99.1 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.75→48.736 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7131 0 43 20 7194
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0037329
X-RAY DIFFRACTIONf_angle_d0.6649921
X-RAY DIFFRACTIONf_dihedral_angle_d3.6725255
X-RAY DIFFRACTIONf_chiral_restr0.0411086
X-RAY DIFFRACTIONf_plane_restr0.0041302
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.75-2.84830.36231930.30773749X-RAY DIFFRACTION99
2.8483-2.96230.33441870.25983771X-RAY DIFFRACTION100
2.9623-3.09710.30542160.2423764X-RAY DIFFRACTION100
3.0971-3.26040.30042090.23123771X-RAY DIFFRACTION100
3.2604-3.46460.31822030.26543681X-RAY DIFFRACTION97
3.4646-3.7320.29632230.24043720X-RAY DIFFRACTION98
3.732-4.10740.25041810.21443748X-RAY DIFFRACTION97
4.1074-4.70130.22882180.17113851X-RAY DIFFRACTION100
4.7013-5.92150.22471980.18033938X-RAY DIFFRACTION100
5.9215-48.7360.22582170.18574133X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -18.7681 Å / Origin y: 65.107 Å / Origin z: 6.5414 Å
111213212223313233
T0.0487 Å2-0.1452 Å2-0.0784 Å2-0.3555 Å20.0258 Å2--0.1781 Å2
L0.0404 °2-0.0078 °20.0393 °2-0.0355 °2-0.006 °2--0.0778 °2
S-0.0331 Å °0.0043 Å °-0.0023 Å °0.0743 Å °-0.01 Å °-0.022 Å °-0.053 Å °0.1798 Å °-0.0393 Å °
Refinement TLS groupSelection details: all

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