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- PDB-4zx9: X-ray crystal structure of PfA-M17 in complex with hydroxamic aci... -

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Basic information

Entry
Database: PDB / ID: 4zx9
TitleX-ray crystal structure of PfA-M17 in complex with hydroxamic acid-based inhibitor 10b
ComponentsProbable M17 family aminopeptidase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / M17 LEUCYL-AMINOPEPTIDASE / PROTEASE / INHIBITOR / HYDROXAMIC ACID / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


leucyl aminopeptidase / metalloaminopeptidase activity / manganese ion binding / proteolysis / cytoplasm
Similarity search - Function
Peptidase M17, leucine aminopeptidase / Cytosol aminopeptidase signature. / Peptidase M17, leucyl aminopeptidase, C-terminal / Peptidase M17, leucine aminopeptidase/peptidase B / Cytosol aminopeptidase family, catalytic domain / Leucine Aminopeptidase, subunit E, domain 1 / Leucine Aminopeptidase, subunit E; domain 1 / Zn peptidases / Aminopeptidase / Macro domain-like ...Peptidase M17, leucine aminopeptidase / Cytosol aminopeptidase signature. / Peptidase M17, leucyl aminopeptidase, C-terminal / Peptidase M17, leucine aminopeptidase/peptidase B / Cytosol aminopeptidase family, catalytic domain / Leucine Aminopeptidase, subunit E, domain 1 / Leucine Aminopeptidase, subunit E; domain 1 / Zn peptidases / Aminopeptidase / Macro domain-like / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-4TK / CARBONATE ION / leucyl aminopeptidase
Similarity search - Component
Biological speciesPlasmodium falciparum FcB1/Columbia (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsDrinkwater, N. / McGowan, S.
Funding support Australia, 1items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)1063786 Australia
CitationJournal: Eur.J.Med.Chem. / Year: 2016
Title: Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions.
Authors: Drinkwater, N. / Vinh, N.B. / Mistry, S.N. / Bamert, R.S. / Ruggeri, C. / Holleran, J.P. / Loganathan, S. / Paiardini, A. / Charman, S.A. / Powell, A.K. / Avery, V.M. / McGowan, S. / Scammells, P.J.
History
DepositionMay 20, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 30, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2017Group: Author supporting evidence / Data collection ...Author supporting evidence / Data collection / Database references / Derived calculations
Category: citation / diffrn_source ...citation / diffrn_source / pdbx_audit_support / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _diffrn_source.pdbx_synchrotron_site ..._citation.journal_id_CSD / _diffrn_source.pdbx_synchrotron_site / _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.2Jan 8, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Probable M17 family aminopeptidase
B: Probable M17 family aminopeptidase
C: Probable M17 family aminopeptidase
D: Probable M17 family aminopeptidase
E: Probable M17 family aminopeptidase
F: Probable M17 family aminopeptidase
G: Probable M17 family aminopeptidase
H: Probable M17 family aminopeptidase
I: Probable M17 family aminopeptidase
J: Probable M17 family aminopeptidase
K: Probable M17 family aminopeptidase
L: Probable M17 family aminopeptidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)708,700101
Polymers695,78712
Non-polymers12,91489
Water23,5101305
1
A: Probable M17 family aminopeptidase
B: Probable M17 family aminopeptidase
C: Probable M17 family aminopeptidase
D: Probable M17 family aminopeptidase
E: Probable M17 family aminopeptidase
F: Probable M17 family aminopeptidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)354,02547
Polymers347,8936
Non-polymers6,13241
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area27560 Å2
ΔGint-133 kcal/mol
Surface area95260 Å2
MethodPISA
2
G: Probable M17 family aminopeptidase
H: Probable M17 family aminopeptidase
I: Probable M17 family aminopeptidase
J: Probable M17 family aminopeptidase
K: Probable M17 family aminopeptidase
L: Probable M17 family aminopeptidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)354,67554
Polymers347,8936
Non-polymers6,78248
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area27890 Å2
ΔGint-130 kcal/mol
Surface area95350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)173.849, 176.970, 229.862
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 12 molecules ABCDEFGHIJKL

#1: Protein
Probable M17 family aminopeptidase


Mass: 57982.230 Da / Num. of mol.: 12 / Fragment: UNP residues 84-605 / Mutation: D152N,D515N,D516N
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum FcB1/Columbia (eukaryote)
Strain: isolate FcB1 / Columbia / Plasmid: PTRCHIS-2B / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 / References: UniProt: A0A024V0B1, leucyl aminopeptidase

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Non-polymers , 8 types, 1394 molecules

#2: Chemical
ChemComp-4TK / N-[(1R)-1-(4-bromophenyl)-2-(hydroxyamino)-2-oxoethyl]-2,2-dimethylpropanamide


Mass: 329.190 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C13H17BrN2O3
#3: Chemical...
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 24 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-CO3 / CARBONATE ION


Mass: 60.009 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: CO3
#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical
ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400


Mass: 238.278 Da / Num. of mol.: 20 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#7: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: SO4
#8: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1305 / Source method: isolated from a natural source / Formula: H2O

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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: 2.56 Å3/Da / Density % sol: 51.94 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 40% (v/v) PEG 400, 0.1 M Tris pH 8.5, 0.2 M Li2SO4

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.9537 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 17, 2014
RadiationMonochromator: DOUBLE CRYSTAL SILICON 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 2.6→48.48 Å / Num. obs: 195787 / % possible obs: 90.7 % / Redundancy: 7.7 % / Biso Wilson estimate: 28.44 Å2 / CC1/2: 0.983 / Rmerge(I) obs: 0.284 / Rpim(I) all: 0.097 / Net I/σ(I): 5.4 / Num. measured all: 1499465 / Scaling rejects: 1011
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allCC1/2Rpim(I) all% possible all
2.6-2.647.51.4261.47427299080.5350.50493.1
14.24-48.487.80.05312.4917911830.9980.01981.6

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Processing

Software
NameVersionClassification
PHENIX1.8.4_1496refinement
Blu-Icedata collection
MOSFLMdata reduction
PHASERphasing
Aimlessdata scaling
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3KQZ

3kqz


Resolution: 2.6→46.742 Å / FOM work R set: 0.739 / SU ML: 0.39 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 32.45 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2666 9738 4.99 %
Rwork0.2205 185535 -
obs0.2228 195273 89.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 98.54 Å2 / Biso mean: 32.61 Å2 / Biso min: 8.7 Å2
Refinement stepCycle: final / Resolution: 2.6→46.742 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms46800 0 605 1305 48710
Biso mean--35.46 30.11 -
Num. residues----6170
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00248250
X-RAY DIFFRACTIONf_angle_d0.58565446
X-RAY DIFFRACTIONf_chiral_restr0.0237538
X-RAY DIFFRACTIONf_plane_restr0.0028290
X-RAY DIFFRACTIONf_dihedral_angle_d11.87217133
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.6-2.62950.40023630.3296243660692
2.6295-2.66050.43083160.32746314663093
2.6605-2.69290.38333410.32036280662192
2.6929-2.7270.34623060.31746354666092
2.727-2.76290.36653150.3066293660892
2.7629-2.80070.36923150.30436285660092
2.8007-2.84070.34253260.29586277660392
2.8407-2.88310.33213300.29126299662992
2.8831-2.92820.31093320.28196230656292
2.9282-2.97620.313260.27876278660492
2.9762-3.02750.34223250.27326286661192
3.0275-3.08250.3152960.2686263655992
3.0825-3.14180.33573490.27386227657691
3.1418-3.20590.33233410.25556208654991
3.2059-3.27560.31463040.24626267657191
3.2756-3.35180.31073150.22956233654891
3.3518-3.43560.27783130.22676164647790
3.4356-3.52840.28163880.22646129651790
3.5284-3.63220.26163220.21396163648590
3.6322-3.74940.2532870.20186197648490
3.7494-3.88340.22023160.18516147646389
3.8834-4.03880.20433180.17916131644989
4.0388-4.22250.22913390.16686104644389
4.2225-4.44490.20053460.15336070641688
4.4449-4.72320.19523470.15436015636288
4.7232-5.08740.19152950.15786120641588
5.0874-5.59860.21912740.17136057633187
5.5986-6.4070.20883420.18446031637387
6.407-8.06540.1993370.16866000633786
8.0654-46.74930.18893140.16855870618481

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