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- PDB-4x2u: X-ray crystal structure of the orally available aminopeptidase in... -

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Basic information

Entry
Database: PDB / ID: 4x2u
TitleX-ray crystal structure of the orally available aminopeptidase inhibitor, Tosedostat, bound to the M1 Alanyl Aminopeptidase from P. falciparum
ComponentsM1 family aminopeptidase
KeywordsHydrolase/Hydrolase Inhibitor / M1 ALANYL-AMINOPEPTIDASE / PROTEASE / INHIBITOR / ANTIMALARIAL / PLASMODIUM FALCIPARUM / TOSEDOSTAT / 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-TOD / Aminopeptidase N
Similarity search - Component
Biological speciesPlasmodium falciparum FcB1/Columbia (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.5 Å
AuthorsDrinkwater, N. / McGowan, S.
Funding support Australia, 2items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)1063786 Australia
Australian Research Council (ARC)FT100100690 Australia
CitationJournal: Proteins / Year: 2015
Title: X-ray crystal structures of an orally available aminopeptidase inhibitor, Tosedostat, bound to anti-malarial drug targets PfA-M1 and PfA-M17.
Authors: Drinkwater, N. / Bamert, R.S. / Sivaraman, K.K. / Paiardini, A. / McGowan, S.
History
DepositionNov 27, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 18, 2015Provider: repository / Type: Initial release
Revision 1.1Apr 8, 2015Group: Database references
Revision 1.2Sep 20, 2017Group: Author supporting evidence / Data collection ...Author supporting evidence / Data collection / Database references / Derived calculations / Refinement description / Source and taxonomy
Category: citation / diffrn_source ...citation / diffrn_source / entity_src_gen / pdbx_audit_support / pdbx_struct_oper_list / software
Item: _citation.journal_id_CSD / _diffrn_source.pdbx_synchrotron_site ..._citation.journal_id_CSD / _diffrn_source.pdbx_synchrotron_site / _entity_src_gen.pdbx_alt_source_flag / _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Sep 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 / diffrn_radiation_wavelength / pdbx_initial_refinement_model / pdbx_struct_conn_angle / refine_hist / 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.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _refine_hist.d_res_high / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_symmetry

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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)104,86915
Polymers103,6321
Non-polymers1,23814
Water22,5731253
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)75.472, 108.675, 118.428
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Detailsbiological unit is the same as asym. / biological unit is ta monomer

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Components

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Protein , 1 types, 1 molecules A

#1: Protein M1 family aminopeptidase / Pfa-M1


Mass: 103631.609 Da / Num. of mol.: 1 / Fragment: UNP residues 196 to 1084 / Mutation: N213Q, N223Q, H378P, N501Q, N745Q, N795Q, N1069Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum FcB1/Columbia (eukaryote)
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, 1267 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-TOD / (2S)-({(2R)-2-[(1S)-1-hydroxy-2-(hydroxyamino)-2-oxoethyl]-4-methylpentanoyl}amino)(phenyl)ethanoic acid


Mass: 338.356 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H22N2O6
#4: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1253 / 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: 2.34 Å3/Da / Density % sol: 47.51 %
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 315r / Detector: CCD / Date: Sep 1, 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: 1.5→46.59 Å / Num. obs: 152905 / % possible obs: 99.6 % / Redundancy: 13.3 % / Biso Wilson estimate: 15.72 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.098 / Rpim(I) all: 0.027 / Net I/σ(I): 19.4 / Num. measured all: 1701152 / Scaling rejects: 72
Reflection shellResolution: 1.5→1.63 Å / Redundancy: 11.9 % / Rmerge(I) obs: 1.067 / Mean I/σ(I) obs: 2.5 / Num. measured all: 72529 / Num. unique all: 6101 / CC1/2: 0.738 / Rpim(I) all: 0.308 / Rejects: 0 / % possible all: 97

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Processing

Software
NameVersionClassification
Aimless0.1.27data scaling
PHENIXrefinement
PDB_EXTRACT3.15data extraction
PHASERphasing
RefinementStarting model: PDB entry 3EBG

3ebg


Resolution: 1.5→37.104 Å / FOM work R set: 0.8845 / SU ML: 0.17 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 18.75 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.188 7612 4.98 %
Rwork0.1568 145293 -
obs0.1584 152905 98.11 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 77.44 Å2 / Biso mean: 21.9 Å2 / Biso min: 7.51 Å2
Refinement stepCycle: final / Resolution: 1.5→37.104 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7226 0 77 1253 8556
Biso mean--40.13 34.74 -
Num. residues----889
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0167586
X-RAY DIFFRACTIONf_angle_d1.63910290
X-RAY DIFFRACTIONf_chiral_restr0.1131137
X-RAY DIFFRACTIONf_plane_restr0.0091312
X-RAY DIFFRACTIONf_dihedral_angle_d13.5822868
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 (%)
1.5-1.51710.29812070.28784157436485
1.5171-1.53490.33582280.28644323455189
1.5349-1.55360.34342110.26454500471192
1.5536-1.57330.26282510.2514617486894
1.5733-1.5940.27582370.23244641487896
1.594-1.61580.25382580.22194742500097
1.6158-1.63890.25862730.21074735500897
1.6389-1.66340.22532360.19814783501998
1.6634-1.68940.24132570.19034829508698
1.6894-1.71710.2222770.18294845512299
1.7171-1.74670.21562170.17874878509599
1.7467-1.77840.22372410.17449155156100
1.7784-1.81260.20992530.171649245177100
1.8126-1.84960.21812320.168849115143100
1.8496-1.88980.21782460.170349115157100
1.8898-1.93380.2162600.183349155175100
1.9338-1.98220.19692600.161949105170100
1.9822-2.03580.17412620.148249205182100
2.0358-2.09570.17422820.143748825164100
2.0957-2.16330.1632720.138449145186100
2.1633-2.24060.19522580.144849255183100
2.2406-2.33030.18642630.1549365199100
2.3303-2.43630.18132510.148349595210100
2.4363-2.56470.17752760.151649295205100
2.5647-2.72540.18282630.152749775240100
2.7254-2.93570.17982680.150649605228100
2.9357-3.2310.18862620.145250085270100
3.231-3.69820.15982510.130750375288100
3.6982-4.65790.14492550.125750725327100
4.6579-37.11520.16693050.149452385543100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.0981-0.335-0.13340.80730.24060.6628-0.1004-0.11130.17450.01780.0310.0223-0.1123-0.05320.0520.14480.0273-0.03230.0981-0.01360.12819.901525.157117.2969
20.31940.1025-0.02991.21570.31320.9869-0.02740.04590.0214-0.0478-0.01220.1744-0.0096-0.11890.03390.06770.0013-0.00470.11230.00160.09647.5886-4.7149-0.0741
30.3226-0.1089-0.05790.91540.15180.4567-0.0346-0.04090.00950.0760.025-0.12310.02460.10790.01180.07160.009-0.00670.12490.00960.102332.3246-6.278413.4338
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 196 through 483 )A0
2X-RAY DIFFRACTION2chain 'A' and (resid 484 through 760 )A0
3X-RAY DIFFRACTION3chain 'A' and (resid 761 through 1084 )A0

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