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- PDB-4zx4: X-ray crystal structure of PfA-M1 in complex with hydroxamic acid... -

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Basic information

Entry
Database: PDB / ID: 4zx4
TitleX-ray crystal structure of PfA-M1 in complex with hydroxamic acid-based inhibitor 10o
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 / chloroplast / proteolysis / zinc ion binding ...symbiont-containing vacuole membrane / vacuolar lumen / Hydrolases; Acting on peptide bonds (peptidases); Aminopeptidases / food vacuole / dipeptidase activity / metalloaminopeptidase activity / aminopeptidase activity / chloroplast / proteolysis / zinc ion binding / membrane / nucleus / cytoplasm
Similarity search - Function
Peptidase M1, alanyl aminopeptidase, C-terminal domain / Aminopeptidase N, middle-beta 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 ...Peptidase M1, alanyl aminopeptidase, C-terminal domain / Aminopeptidase N, middle-beta 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 / Aminopeptidase N-like , N-terminal domain / Peptidase M1, alanine aminopeptidase/leukotriene A4 hydrolase / Peptidase M1, membrane alanine aminopeptidase / 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-4TL / PHOSPHATE ION / Aminopeptidase N
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 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 / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr2_auth_seq_id

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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)104,83611
Polymers103,7611
Non-polymers1,07610
Water17,150952
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)75.150, 109.190, 118.830
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 , 7 types, 962 molecules

#2: Chemical ChemComp-4TL / N-[(1R)-2-(hydroxyamino)-2-oxo-1-(3',4',5'-trifluorobiphenyl-4-yl)ethyl]-2,2-dimethylpropanamide


Mass: 380.361 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H19F3N2O3
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#7: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 952 / 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: 47.71 %
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: 1.9→34.04 Å / Num. obs: 77709 / % possible obs: 100 % / Redundancy: 7.8 % / Biso Wilson estimate: 20.93 Å2 / CC1/2: 0.994 / Rmerge(I) obs: 0.17 / Rpim(I) all: 0.064 / Net I/σ(I): 9.4 / Num. measured all: 603243 / Scaling rejects: 55
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allCC1/2Rpim(I) all% possible all
1.9-1.947.51.271.83400645220.5980.485100
9.5-34.046.50.10321.345537040.9860.04398

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Processing

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

3ebg


Resolution: 1.9→34.04 Å / FOM work R set: 0.8819 / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 18.81 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1972 3938 5.07 %
Rwork0.1577 73692 -
obs0.1597 77630 99.99 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 95.79 Å2 / Biso mean: 24.64 Å2 / Biso min: 8.8 Å2
Refinement stepCycle: final / Resolution: 1.9→34.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7248 0 64 952 8264
Biso mean--41.59 33.9 -
Num. residues----889
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0137572
X-RAY DIFFRACTIONf_angle_d1.2810267
X-RAY DIFFRACTIONf_chiral_restr0.0611126
X-RAY DIFFRACTIONf_plane_restr0.0071311
X-RAY DIFFRACTIONf_dihedral_angle_d13.7322864
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 28 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
1.9-1.92320.25831330.230925992732
1.9232-1.94750.26781470.227825822729
1.9475-1.97320.28831430.21926052748
1.9732-2.00020.25981210.208525972718
2.0002-2.02880.26581310.207326172748
2.0288-2.0590.25391630.191925662729
2.059-2.09120.22581310.198226322763
2.0912-2.12550.23561590.175725732732
2.1255-2.16210.22381490.175725962745
2.1621-2.20140.23521500.163126282778
2.2014-2.24380.23481230.164625962719
2.2438-2.28960.20421400.161726092749
2.2896-2.33930.24531420.167926372779
2.3393-2.39370.2091240.163425972721
2.3937-2.45360.25011280.160626342762
2.4536-2.51990.21561520.159526222774
2.5199-2.5940.21541510.160226302781
2.594-2.67770.18131250.154925972722
2.6777-2.77340.21911490.159626382787
2.7734-2.88440.2051390.162226442783
2.8844-3.01560.2131450.157526252770
3.0156-3.17450.19681280.160526472775
3.1745-3.37320.18021450.148226442789
3.3732-3.63340.15731190.13926802799
3.6334-3.99850.16561540.138126632817
3.9985-4.57590.17071280.124827022830
4.5759-5.76060.14711500.129427192869
5.7606-34.04650.15261690.156128132982
Refinement TLS params.Method: refined / Origin x: 17.7364 Å / Origin y: 113.0849 Å / Origin z: 129.0445 Å
111213212223313233
T0.1036 Å2-0.0064 Å20.0227 Å2-0.121 Å20.0098 Å2--0.0989 Å2
L0.4539 °2-0.1932 °20.0724 °2-0.7613 °20.1013 °2--0.5395 °2
S-0.0612 Å °-0.0074 Å °0.0021 Å °0.0205 Å °0.0295 Å °-0.0173 Å °-0.0539 Å °-0.003 Å °0.0288 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA196 - 1084
2X-RAY DIFFRACTION1allB1
3X-RAY DIFFRACTION1allC1 - 9
4X-RAY DIFFRACTION1allD1 - 957

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