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

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Basic information

Entry
Database: PDB / ID: 8fjt
TitleHuman mitochondrial serine hydroxymethyltransferase (SHMT2) in complex with PLP, glycine and AGF362 inhibitor
ComponentsSerine hydroxymethyltransferase, mitochondrial
KeywordsTRANSFERASE/INHIBITOR / SHMT2 / 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 / Metabolism of folate and pterines ...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 / Metabolism of folate and pterines / regulation of oxidative phosphorylation / 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 / 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 / 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 / Chem-PLG / PYRIDOXAL-5'-PHOSPHATE / Chem-Y72 / Serine hydroxymethyltransferase, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.47 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: J.Med.Chem. / Year: 2023
Title: Structure-Based Design of Transport-Specific Multitargeted One-Carbon Metabolism Inhibitors in Cytosol and Mitochondria.
Authors: Nayeen, M.J. / Katinas, J.M. / Magdum, T. / Shah, K. / Wong, J.E. / O'Connor, C.E. / Fifer, A.N. / Wallace-Povirk, A. / Hou, Z. / Matherly, L.H. / Dann 3rd, C.E. / Gangjee, A.
History
DepositionDec 20, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 6, 2023Provider: repository / Type: Initial release
Revision 2.0Feb 7, 2024Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Refinement description / Structure summary
Category: atom_site / database_PDB_caveat ...atom_site / database_PDB_caveat / entity / pdbx_nonpoly_scheme / pdbx_poly_seq_scheme / pdbx_struct_assembly_prop / pdbx_struct_sheet_hbond / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / pdbx_validate_rmsd_angle / pdbx_validate_torsion / refine / refine_hist / refine_ls_shell / struct_conf / struct_conn / struct_sheet / struct_sheet_order / struct_sheet_range
Item: _entity.details / _pdbx_nonpoly_scheme.auth_mon_id ..._entity.details / _pdbx_nonpoly_scheme.auth_mon_id / _pdbx_nonpoly_scheme.auth_seq_num / _pdbx_poly_seq_scheme.auth_mon_id / _pdbx_poly_seq_scheme.auth_seq_num / _pdbx_poly_seq_scheme.pdb_mon_id / _pdbx_struct_assembly_prop.value / _refine.ls_R_factor_R_free / _refine.ls_R_factor_R_work / _refine.ls_R_factor_obs / _refine.ls_d_res_low / _refine.ls_percent_reflns_obs / _refine_hist.d_res_low / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_ligand / _refine_hist.pdbx_number_atoms_protein / _refine_ls_shell.d_res_low / _struct_conf.end_auth_comp_id / _struct_conf.end_auth_seq_id / _struct_conf.end_label_comp_id / _struct_conf.end_label_seq_id / _struct_conf.pdbx_PDB_helix_length / _struct_conn.pdbx_value_order
Description: Sequence discrepancy
Details: Removed Pro301, which should resolve the linkage issue between ProA301 and ThrA303
Provider: author / Type: Coordinate replacement

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)110,7997
Polymers109,2122
Non-polymers1,5875
Water4,360242
1


  • Idetical with deposited unit
  • defined by software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10390 Å2
ΔGint-44 kcal/mol
Surface area30770 Å2
MethodPISA
Unit cell
Length a, b, c (Å)160.389, 160.389, 208.748
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number179
Space group name H-MP6522
Components on special symmetry positions
IDModelComponents
11A-842-

HOH

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Components

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Protein , 1 types, 2 molecules AB

#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

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Non-polymers , 5 types, 247 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.: 1 / Source method: obtained synthetically / Formula: C10H15N2O7P
#3: 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.: 2 / Source method: obtained synthetically / Formula: C20H22FN5O6S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-GLY / GLYCINE


Type: peptide linking / Mass: 75.067 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H5NO2
#5: Chemical ChemComp-PLP / PYRIDOXAL-5'-PHOSPHATE / VITAMIN B6 Phosphate


Mass: 247.142 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H10NO6P
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 242 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.55 Å3/Da / Density % sol: 65.35 %
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 10 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: Nov 12, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.47→48.8623 Å / Num. obs: 57316 / % possible obs: 100 % / Redundancy: 12.8 % / CC1/2: 0.995 / Rmerge(I) obs: 0.294 / Rpim(I) all: 0.085 / Rrim(I) all: 0.306 / Net I/σ(I): 9.9
Reflection shellResolution: 2.47→2.54 Å / Rmerge(I) obs: 4.016 / Num. unique obs: 4379 / CC1/2: 0.382 / Rpim(I) all: 1.151 / Rrim(I) all: 4.18

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Processing

Software
NameVersionClassification
PHENIX1.13-2998refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.47→48.85 Å / SU ML: 0.4 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 31.48 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.285 2804 4.92 %
Rwork0.241 --
obs0.244 57003 99.6 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.47→48.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7014 0 106 242 7362
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0027320
X-RAY DIFFRACTIONf_angle_d0.5679914
X-RAY DIFFRACTIONf_dihedral_angle_d3.6975315
X-RAY DIFFRACTIONf_chiral_restr0.0381080
X-RAY DIFFRACTIONf_plane_restr0.0041299
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.47-2.51260.38351300.35452515X-RAY DIFFRACTION94
2.5126-2.55830.33381170.35152643X-RAY DIFFRACTION98
2.5583-2.60750.40131360.34932649X-RAY DIFFRACTION99
2.6075-2.66070.39381260.3362691X-RAY DIFFRACTION100
2.6607-2.71860.38581620.31862673X-RAY DIFFRACTION100
2.7186-2.78180.37031430.3252660X-RAY DIFFRACTION100
2.7818-2.85140.37171400.31372678X-RAY DIFFRACTION100
2.8514-2.92840.33781480.28542682X-RAY DIFFRACTION100
2.9284-3.01460.30251280.28332694X-RAY DIFFRACTION100
3.0146-3.11190.34761480.27612681X-RAY DIFFRACTION100
3.1119-3.22310.3041560.26722675X-RAY DIFFRACTION100
3.2231-3.35210.33741360.26442708X-RAY DIFFRACTION100
3.3521-3.50460.25491230.24862738X-RAY DIFFRACTION100
3.5046-3.68940.26951280.23382720X-RAY DIFFRACTION100
3.6894-3.92040.2731620.2122714X-RAY DIFFRACTION100
3.9204-4.22290.24621300.20392757X-RAY DIFFRACTION100
4.2229-4.64760.23521310.19892752X-RAY DIFFRACTION100
4.6476-5.31940.2531520.19722772X-RAY DIFFRACTION100
5.3194-6.69920.27581540.2242813X-RAY DIFFRACTION100
6.6992-48.850.21671540.18992984X-RAY DIFFRACTION100

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