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- PDB-4x2t: X-ray crystal structure of the orally available aminopeptidase in... -

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Basic information

Entry
Database: PDB / ID: 4x2t
TitleX-ray crystal structure of the orally available aminopeptidase inhibitor, Tosedostat, bound to the M17 Leucyl Aminopeptidase from P. falciparum
ComponentsM17 leucyl aminopeptidase
KeywordsHydrolase/Hydrolase Inhibitor / M17 LEUCYL-AMINOPEPTIDASE / PROTEASE / INHIBITOR / TOSEDOSTAT / ANTIMALARIAL / PLASMODIUM FALCIPARUM / Hydrolase-Hydrolase Inhibitor complex
Function / homology
Function and homology information


Hydrolases; Acting on peptide bonds (peptidases); Dipeptidases / leucyl aminopeptidase / metallodipeptidase activity / peptide catabolic process / metalloaminopeptidase activity / carboxypeptidase activity / peptidase activity / manganese ion binding / proteolysis / zinc ion binding ...Hydrolases; Acting on peptide bonds (peptidases); Dipeptidases / leucyl aminopeptidase / metallodipeptidase activity / peptide catabolic process / metalloaminopeptidase activity / carboxypeptidase activity / peptidase activity / manganese ion binding / proteolysis / zinc ion binding / metal ion binding / identical protein binding / cytosol / 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
CARBONATE ION / Chem-TOD / Leucine aminopeptidase
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.729 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 / 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_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.value / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _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 / _struct_conn.ptnr2_label_seq_id
Revision 1.5Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)700,41982
Polymers690,77612
Non-polymers9,64370
Water18,5731031
1
A: M17 leucyl aminopeptidase
B: M17 leucyl aminopeptidase
C: M17 leucyl aminopeptidase
D: M17 leucyl aminopeptidase
E: M17 leucyl aminopeptidase
F: M17 leucyl aminopeptidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)350,66144
Polymers345,3886
Non-polymers5,27338
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area32800 Å2
ΔGint-500 kcal/mol
Surface area96490 Å2
MethodPISA
2
G: M17 leucyl aminopeptidase
H: M17 leucyl aminopeptidase
I: M17 leucyl aminopeptidase
J: M17 leucyl aminopeptidase
K: M17 leucyl aminopeptidase
L: M17 leucyl aminopeptidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)349,75838
Polymers345,3886
Non-polymers4,37032
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area29880 Å2
ΔGint-493 kcal/mol
Surface area97410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)173.715, 176.698, 223.977
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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, 12 molecules ABCDEFGHIJKL

#1: Protein
M17 leucyl aminopeptidase


Mass: 57564.648 Da / Num. of mol.: 12 / Fragment: UNP residues 85 to 603 / Mutation: N152Q, N515Q, N545Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (isolate 3D7) (eukaryote)
Strain: isolate 3D7 / Gene: LAP, PF14_0439 / Plasmid: PTRCHIS-2B / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 / References: UniProt: Q8IL11

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Non-polymers , 6 types, 1101 molecules

#2: Chemical...
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 24 / 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.: 11 / Source method: obtained synthetically / Formula: C16H22N2O6
#4: Chemical
ChemComp-CO3 / CARBONATE ION


Mass: 60.009 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: CO3
#5: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: SO4
#6: Chemical
ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400


Mass: 238.278 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1031 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY

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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: 2.49 Å3/Da / Density % sol: 50.57 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.6 / Details: 35% (v/v) PEG 400, 0.1 M Tris pH 8.6, 0.2 M Li2SO4 / Temp details: 20 degrees celcius

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 1.12819 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 15, 2013
RadiationMonochromator: DOUBLE CRYSTAL SILICON 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.12819 Å / Relative weight: 1
ReflectionResolution: 2.729→48.75 Å / Num. obs: 181046 / % possible obs: 99.1 % / Redundancy: 3.7 % / Biso Wilson estimate: 27.01 Å2 / CC1/2: 0.99 / Rpim(I) all: 0.08 / Net I/σ(I): 7.7 / Num. measured all: 664861
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
2.73-2.783.40.4652.52663877490.8350.28786.5
14.95-48.753.50.05213.1401711600.9970.03394.4

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine: 1.8.4_1496)refinement
Aimless0.1.29data scaling
PDB_EXTRACT3.15data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 3KQX

3kqx


Resolution: 2.729→48.748 Å / SU ML: 0.35 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 30.12 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2737 9105 5.03 %
Rwork0.2198 --
obs0.2225 180843 98.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.729→48.748 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms46554 0 467 1031 48052
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00847877
X-RAY DIFFRACTIONf_angle_d1.2964969
X-RAY DIFFRACTIONf_dihedral_angle_d12.78516830
X-RAY DIFFRACTIONf_chiral_restr0.0877528
X-RAY DIFFRACTIONf_plane_restr0.0088217
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7292-2.76020.34442510.28944608X-RAY DIFFRACTION80
2.7602-2.79260.32733140.25395702X-RAY DIFFRACTION100
2.7926-2.82670.3453100.25655706X-RAY DIFFRACTION100
2.8267-2.86250.29082800.24755738X-RAY DIFFRACTION100
2.8625-2.90010.33753030.24535723X-RAY DIFFRACTION100
2.9001-2.93980.30643230.2455738X-RAY DIFFRACTION100
2.9398-2.98180.29073070.24565725X-RAY DIFFRACTION100
2.9818-3.02630.31043070.24165692X-RAY DIFFRACTION100
3.0263-3.07360.2983070.24485718X-RAY DIFFRACTION100
3.0736-3.1240.31553300.25015737X-RAY DIFFRACTION100
3.124-3.17790.28182790.23665752X-RAY DIFFRACTION100
3.1779-3.23560.32362960.24155727X-RAY DIFFRACTION100
3.2356-3.29790.32743070.25295763X-RAY DIFFRACTION100
3.2979-3.36520.28572600.24075747X-RAY DIFFRACTION100
3.3652-3.43830.30163140.23635750X-RAY DIFFRACTION100
3.4383-3.51830.29512970.2385756X-RAY DIFFRACTION100
3.5183-3.60620.29433060.23225742X-RAY DIFFRACTION100
3.6062-3.70370.28563180.22655754X-RAY DIFFRACTION100
3.7037-3.81260.26322680.21435784X-RAY DIFFRACTION100
3.8126-3.93570.24193130.20475801X-RAY DIFFRACTION100
3.9357-4.07630.24152940.20265741X-RAY DIFFRACTION100
4.0763-4.23940.26983080.20415773X-RAY DIFFRACTION100
4.2394-4.43220.22612990.1845768X-RAY DIFFRACTION100
4.4322-4.66570.23213230.18425759X-RAY DIFFRACTION99
4.6657-4.95780.23253180.18265781X-RAY DIFFRACTION100
4.9578-5.34010.24092940.19135833X-RAY DIFFRACTION100
5.3401-5.87670.26063090.20465836X-RAY DIFFRACTION100
5.8767-6.72520.26233250.21625843X-RAY DIFFRACTION100
6.7252-8.46580.22183170.19815898X-RAY DIFFRACTION100
8.4658-48.75590.23143280.19985843X-RAY DIFFRACTION95
Refinement TLS params.Method: refined / Origin x: 89.2636 Å / Origin y: 56.0604 Å / Origin z: 77.9968 Å
111213212223313233
T0.1534 Å2-0.0048 Å20.019 Å2-0.1712 Å20.016 Å2--0.3115 Å2
L0.0267 °2-0.007 °2-0.0146 °2--0.0018 °2-0.0084 °2--0.0792 °2
S-0.0068 Å °-0.0144 Å °0.1997 Å °0.0115 Å °0.031 Å °-0.0463 Å °0.0038 Å °0.0047 Å °0.0052 Å °
Refinement TLS groupSelection details: all

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