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- PDB-4zw8: X-ray crystal structure of PfA-M1 in complex with hydroxamic acid... -

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Basic information

Entry
Database: PDB / ID: 4zw8
TitleX-ray crystal structure of PfA-M1 in complex with hydroxamic acid-based inhibitor 9r
ComponentsM1 family aminopeptidase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / M1 ALANYL-AMINOPEPTIDASE / PROTEASE / INHIBITOR / HYDROXAMIC ACID / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


symbiont-containing vacuole membrane / vacuolar lumen / Hydrolases; Acting on peptide bonds (peptidases); Aminopeptidases / food vacuole / dipeptidase activity / metalloaminopeptidase activity / aminopeptidase activity / proteolysis / zinc ion binding / nucleus ...symbiont-containing vacuole membrane / vacuolar lumen / Hydrolases; Acting on peptide bonds (peptidases); Aminopeptidases / food vacuole / dipeptidase activity / metalloaminopeptidase activity / aminopeptidase activity / proteolysis / zinc ion binding / nucleus / membrane / cytoplasm
Similarity search - Function
Aminopeptidase N, middle-beta domain / Peptidase M1, alanyl aminopeptidase, C-terminal domain / Peptidase M1, alanyl aminopeptidase / Peptidase M1, alanyl aminopeptidase, C-terminal / Peptidase M1, alanyl aminopeptidase, Ig-like fold / Peptidase M1, alanyl aminopeptidase, C-terminal domain superfamily / Alanyl aminopeptidase, Ig-like domain superfamily / Domain of unknown function (DUF3458) Ig-like fold / Domain of unknown function (DUF3458_C) ARM repeats / Zincin-like fold ...Aminopeptidase N, middle-beta domain / Peptidase M1, alanyl aminopeptidase, C-terminal domain / Peptidase M1, alanyl aminopeptidase / Peptidase M1, alanyl aminopeptidase, C-terminal / Peptidase M1, alanyl aminopeptidase, Ig-like fold / Peptidase M1, alanyl aminopeptidase, C-terminal domain superfamily / Alanyl aminopeptidase, Ig-like domain superfamily / Domain of unknown function (DUF3458) Ig-like fold / Domain of unknown function (DUF3458_C) ARM repeats / Zincin-like fold / Zincin-like - #30 / Zincin-like / tricorn interacting facor f3 domain / Peptidase M1, alanine aminopeptidase/leukotriene A4 hydrolase / Peptidase M1, membrane alanine aminopeptidase / Aminopeptidase N-like , N-terminal domain / Peptidase family M1 domain / Peptidase M1 N-terminal domain / Aminopeptidase N-like , N-terminal domain superfamliy / Neutral Protease Domain 2 / Neutral Protease; domain 2 / Peptidase M4/M1, CTD superfamily / Neutral zinc metallopeptidases, zinc-binding region signature. / Alpha Horseshoe / Immunoglobulin-like / Sandwich / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-4T2 / Aminopeptidase N
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 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 19, 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 / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: M1 family aminopeptidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)104,7239
Polymers103,7611
Non-polymers9638
Water16,754930
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)75.530, 109.110, 118.400
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, 1 molecules A

#1: Protein M1 family aminopeptidase / Pfa-M1


Mass: 103760.719 Da / Num. of mol.: 1 / Fragment: UNP residues 195-1084 / Mutation: N213Q, N223Q, H378P, N501Q, N795Q, N1069Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Strain: isolate FcB1 / Columbia / Plasmid: PTRCHIS-2B / Production host: Escherichia coli (E. coli) / Strain (production host): BL21
References: UniProt: O96935, Hydrolases; Acting on peptide bonds (peptidases); Aminopeptidases

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Non-polymers , 5 types, 938 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-4T2 / tert-butyl {(1S)-2-(hydroxyamino)-1-[3'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl]-2-oxoethyl}carbamate


Mass: 400.428 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H24N4O5
#4: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 930 / 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: 2.35 Å3/Da / Density % sol: 47.75 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 22% (v/v) PEG 8000, 10% (v/v) glycerol, 0.1 M Tris pH 8.5, 0.2 M MgCl2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX1 / Wavelength: 0.9537 Å
DetectorType: ADSC QUANTUM 210r / Detector: CCD / Date: Aug 14, 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→35.69 Å / Num. obs: 66805 / % possible obs: 99.9 % / Redundancy: 6.7 % / Biso Wilson estimate: 23.86 Å2 / CC1/2: 0.994 / Rmerge(I) obs: 0.158 / Rpim(I) all: 0.065 / Net I/σ(I): 8.5 / Num. measured all: 447176 / Scaling rejects: 41
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
2-2.0561.1911.52681544510.5930.51399.7
9.38-35.695.80.05321.142877350.9890.02498.4

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Processing

Software
NameVersionClassification
Blu-Icedata collection
MOSFLMdata reduction
Aimless0.3.8data scaling
PHASESphasing
PHENIX1.8.4_1496refinement
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3EBG

3ebg


Resolution: 2→35.688 Å / FOM work R set: 0.8604 / SU ML: 0.22 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 20.97 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2103 3389 5.08 %
Rwork0.1738 63341 -
obs0.1757 66730 99.93 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 102.73 Å2 / Biso mean: 27.11 Å2 / Biso min: 7.34 Å2
Refinement stepCycle: final / Resolution: 2→35.688 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7264 0 58 930 8252
Biso mean--38.82 36.24 -
Num. residues----889
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0037588
X-RAY DIFFRACTIONf_angle_d0.69910287
X-RAY DIFFRACTIONf_chiral_restr0.0281129
X-RAY DIFFRACTIONf_plane_restr0.0041314
X-RAY DIFFRACTIONf_dihedral_angle_d12.9132881
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 24

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2-2.02860.3291320.28032609274199
2.0286-2.05890.27581490.259525822731100
2.0589-2.0910.2741510.239326022753100
2.091-2.12530.25681500.224325742724100
2.1253-2.16190.25221430.216326102753100
2.1619-2.20120.3041490.210425832732100
2.2012-2.24360.26721300.210526332763100
2.2436-2.28940.2551360.205626162752100
2.2894-2.33910.28441360.201826232759100
2.3391-2.39350.22251340.195925902724100
2.3935-2.45340.26511260.193626532779100
2.4534-2.51970.23811530.184326292782100
2.5197-2.59380.23161460.184726162762100
2.5938-2.67750.20911290.183926172746100
2.6775-2.77320.23691440.181726422786100
2.7732-2.88420.23181420.183426282770100
2.8842-3.01540.2391430.17426382781100
3.0154-3.17430.22481300.179626532783100
3.1743-3.3730.22131420.167426462788100
3.373-3.63320.16131260.150126872813100
3.6332-3.99840.17231490.142226752824100
3.9984-4.57590.17341290.133727012830100
4.5759-5.76130.15141480.13427142862100
5.7613-35.69360.15351720.158828202992100
Refinement TLS params.Method: refined / Origin x: 93.2173 Å / Origin y: 113.0877 Å / Origin z: 128.5903 Å
111213212223313233
T0.0751 Å2-0.0034 Å20.0121 Å2-0.0879 Å20.0056 Å2--0.0753 Å2
L0.3575 °2-0.1868 °20.055 °2-0.5321 °20.1105 °2--0.4393 °2
S-0.0574 Å °-0.0086 Å °0.0224 Å °0.0148 Å °0.032 Å °-0.0182 Å °-0.0362 Å °-0.0066 Å °-0.0086 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA196 - 1084
2X-RAY DIFFRACTION1allB1 - 2
3X-RAY DIFFRACTION1allC1 - 6
4X-RAY DIFFRACTION1allD1 - 940

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