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- PDB-5fi2: Crystal structure of human GAC in complex with inhibitor UPGL_000... -

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Basic information

Entry
Database: PDB / ID: 5fi2
TitleCrystal structure of human GAC in complex with inhibitor UPGL_00009: 2-phenyl-~{N}-[5-[[(3~{R})-1-[5-(2-phenylethanoylamino)-1,3,4-thiadiazol- 2-yl]pyrrolidin-3-yl]amino]-1,3,4-thiadiazol-2-yl]ethanamide
ComponentsGlutaminase kidney isoform, mitochondrial
KeywordsHYDROLASE/HYDROLASE INHIBITOR / glutaminase C / complex / inhibitor / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


glutamine catabolic process / glutamate biosynthetic process / regulation of respiratory gaseous exchange by nervous system process / Glutamate and glutamine metabolism / intracellular glutamate homeostasis / Glutamate Neurotransmitter Release Cycle / glutaminase / glutaminase activity / suckling behavior / TP53 Regulates Metabolic Genes ...glutamine catabolic process / glutamate biosynthetic process / regulation of respiratory gaseous exchange by nervous system process / Glutamate and glutamine metabolism / intracellular glutamate homeostasis / Glutamate Neurotransmitter Release Cycle / glutaminase / glutaminase activity / suckling behavior / TP53 Regulates Metabolic Genes / chemical synaptic transmission / protein homotetramerization / mitochondrial matrix / synapse / mitochondrion / cytosol
Similarity search - Function
Recoverin; domain 1 - #210 / Glutaminase, EF-hand domain / EF-hand domain / Glutaminase / Glutaminase / Recoverin; domain 1 / Beta-lactamase / DD-peptidase/beta-lactamase superfamily / Ankyrin repeats (3 copies) / Ankyrin repeat profile. ...Recoverin; domain 1 - #210 / Glutaminase, EF-hand domain / EF-hand domain / Glutaminase / Glutaminase / Recoverin; domain 1 / Beta-lactamase / DD-peptidase/beta-lactamase superfamily / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Beta-lactamase/transpeptidase-like / Orthogonal Bundle / 3-Layer(aba) Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-5XX / Glutaminase kidney isoform, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsHuang, Q. / Cerione, R.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM040654 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM047458 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM061762 United States
CitationJournal: Bioorg.Med.Chem. / Year: 2016
Title: Design and evaluation of novel glutaminase inhibitors.
Authors: McDermott, L.A. / Iyer, P. / Vernetti, L. / Rimer, S. / Sun, J. / Boby, M. / Yang, T. / Fioravanti, M. / O'Neill, J. / Wang, L. / Drakes, D. / Katt, W. / Huang, Q. / Cerione, R.
History
DepositionDec 22, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 11, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 20, 2017Group: Advisory / Author supporting evidence ...Advisory / Author supporting evidence / Database references / Derived calculations
Category: citation / pdbx_audit_support ...citation / pdbx_audit_support / pdbx_struct_oper_list / pdbx_unobs_or_zero_occ_atoms
Item: _citation.journal_id_CSD / _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.2Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Sep 27, 2023Group: Advisory / Data collection ...Advisory / Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_unobs_or_zero_occ_atoms
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Glutaminase kidney isoform, mitochondrial
B: Glutaminase kidney isoform, mitochondrial
C: Glutaminase kidney isoform, mitochondrial
D: Glutaminase kidney isoform, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)238,8726
Polymers237,8304
Non-polymers1,0412
Water12,611700
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8810 Å2
ΔGint-27 kcal/mol
Surface area62400 Å2
2
A: Glutaminase kidney isoform, mitochondrial
D: Glutaminase kidney isoform, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)119,9564
Polymers118,9152
Non-polymers1,0412
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3850 Å2
ΔGint-14 kcal/mol
Surface area31850 Å2
MethodPISA
3
B: Glutaminase kidney isoform, mitochondrial
C: Glutaminase kidney isoform, mitochondrial


Theoretical massNumber of molelcules
Total (without water)118,9152
Polymers118,9152
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3910 Å2
ΔGint-15 kcal/mol
Surface area31600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)98.054, 138.618, 176.313
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein
Glutaminase kidney isoform, mitochondrial / GLS / K-glutaminase / L-glutamine amidohydrolase


Mass: 59457.590 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli) / References: UniProt: O94925
#2: Chemical ChemComp-5XX / 2-phenyl-~{N}-[5-[[(3~{R})-1-[5-(2-phenylethanoylamino)-1,3,4-thiadiazol-2-yl]pyrrolidin-3-yl]amino]-1,3,4-thiadiazol-2-yl]ethanamide


Mass: 520.630 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H24N8O2S2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 700 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.52 Å3/Da / Density % sol: 51.2 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: PEG6000, LiCl, Tris-HCl / PH range: 8.0-8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CHESS / Beamline: A1 / Wavelength: 0.978 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Feb 22, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.978 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. obs: 107128 / % possible obs: 99.9 % / Redundancy: 7.1 % / Rmerge(I) obs: 0.125 / Net I/σ(I): 14.9
Reflection shellResolution: 2.3→2.34 Å / Redundancy: 6.8 % / Mean I/σ(I) obs: 2.2 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.8.4_1496refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5d3o

5d3o


Resolution: 2.5→44.825 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 33.2 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2654 1558 1.87 %Random selection
Rwork0.2247 ---
obs0.2255 83396 99.62 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.5→44.825 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12776 0 72 700 13548
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0113180
X-RAY DIFFRACTIONf_angle_d1.22717788
X-RAY DIFFRACTIONf_dihedral_angle_d15.6374890
X-RAY DIFFRACTIONf_chiral_restr0.0521942
X-RAY DIFFRACTIONf_plane_restr0.0062296
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5-2.58070.35821410.25347382X-RAY DIFFRACTION100
2.5807-2.67290.30421400.26027345X-RAY DIFFRACTION100
2.6729-2.77990.31231410.25387376X-RAY DIFFRACTION100
2.7799-2.90640.27861400.24897383X-RAY DIFFRACTION100
2.9064-3.05960.2981410.24117414X-RAY DIFFRACTION100
3.0596-3.25130.24881410.23477414X-RAY DIFFRACTION100
3.2513-3.50220.2541420.22157435X-RAY DIFFRACTION100
3.5022-3.85450.25221420.20387436X-RAY DIFFRACTION100
3.8545-4.41180.22011420.19427478X-RAY DIFFRACTION100
4.4118-5.55680.24471440.21467538X-RAY DIFFRACTION100
5.5568-44.83230.28511440.22927637X-RAY DIFFRACTION97

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