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

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Basic information

Entry
Database: PDB / ID: 8tlc
TitleHuman mitochondrial serine hydroxymethyltransferase (SHMT2) in complex with PLP, glycine and tri-glutamate AGF347 inhibitor
ComponentsSerine hydroxymethyltransferase, mitochondrial
KeywordsTRANSFERASE / SHMT2 / tetramer / glycine synthesis / inhibitor / polyglutamate
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
: / Serine hydroxymethyltransferase, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.72 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
DepositionJul 26, 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)110,4003
Polymers109,6682
Non-polymers7321
Water18010
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)220,8006
Polymers219,3364
Non-polymers1,4632
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation12_564x,x-y+1,-z-1/61
Buried area22080 Å2
ΔGint-102 kcal/mol
Surface area60610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)158.718, 158.718, 207.155
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


Mass: 54834.043 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
#2: Chemical ChemComp-I6I / N-{4-[4-(2-amino-4-oxo-1,4-dihydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl]-2-fluorobenzoyl}-D-gamma-glutamyl-L-gamma-glutamyl-D-glutamic acid


Mass: 731.682 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H38FN7O12 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 10 / 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: 64.18 %
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: Dec 9, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.72→48.712 Å / Num. obs: 41987 / % possible obs: 100 % / Redundancy: 11.3 % / CC1/2: 0.973 / Rmerge(I) obs: 0.341 / Rpim(I) all: 0.106 / Rrim(I) all: 0.358 / Net I/σ(I): 7.2
Reflection shellResolution: 2.72→2.83 Å / Rmerge(I) obs: 2.073 / Num. unique obs: 4655 / CC1/2: 0.279 / Rpim(I) all: 0.834 / Rrim(I) all: 2.239

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.72→48.712 Å / SU ML: 0.53 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 37.91 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3594 2050 4.9 %
Rwork0.306 --
obs0.3085 41812 99.69 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.72→48.712 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6941 0 52 10 7003
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0047132
X-RAY DIFFRACTIONf_angle_d0.7879669
X-RAY DIFFRACTIONf_dihedral_angle_d7.0454272
X-RAY DIFFRACTIONf_chiral_restr0.0441066
X-RAY DIFFRACTIONf_plane_restr0.0051272
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.72-2.81720.39931880.36173864X-RAY DIFFRACTION99
2.8172-2.930.39481980.35533921X-RAY DIFFRACTION100
2.93-3.06330.41862000.33953924X-RAY DIFFRACTION100
3.0633-3.22480.3922300.35153899X-RAY DIFFRACTION100
3.2248-3.42680.41761910.35423938X-RAY DIFFRACTION100
3.4268-3.69130.42012000.36453931X-RAY DIFFRACTION99
3.6913-4.06260.36472160.31923934X-RAY DIFFRACTION99
4.0626-4.65010.33191860.2744026X-RAY DIFFRACTION100
4.6501-5.8570.30632260.27124045X-RAY DIFFRACTION100
5.857-48.7120.30512150.24114280X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -19.2733 Å / Origin y: 65.1651 Å / Origin z: 6.6913 Å
111213212223313233
T0.3495 Å2-0.1508 Å2-0.3233 Å2-0.6912 Å20.2463 Å2---0.16 Å2
L0.8288 °2-0.3087 °20.7724 °2-1.1178 °2-0.615 °2--1.4954 °2
S-0.3815 Å °-0.2533 Å °0.4899 Å °0.5157 Å °-0.1296 Å °-0.8565 Å °-0.3908 Å °0.3442 Å °-0.108 Å °
Refinement TLS groupSelection details: all

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