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- PDB-4zw5: X-ray crystal structure of PfA-M1 in complex with hydroxamic acid... -

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Basic information

Entry
Database: PDB / ID: 4zw5
TitleX-ray crystal structure of PfA-M1 in complex with hydroxamic acid-based inhibitor 9f
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-4SA / Aminopeptidase N
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.8 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 ...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)104,2175
Polymers103,7611
Non-polymers4564
Water15,997888
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)75.840, 109.100, 117.960
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#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
#2: Chemical ChemComp-ZN / ZINC ION


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


Mass: 342.389 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H22N2O4
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 888 / 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: 47.76 %
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: 1 Å
DetectorType: ADSC QUANTUM 210r / Detector: CCD / Date: Jul 2, 2014
RadiationMonochromator: DOUBLE CRYSTAL SILICON 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→80.09 Å / Num. obs: 91013 / % possible obs: 99.8 % / Redundancy: 7 % / Biso Wilson estimate: 18.76 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.23 / Rpim(I) all: 0.093 / Net I/σ(I): 10.7 / Num. measured all: 639842 / Scaling rejects: 577
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
1.8-1.836.72.62822969444370.4051.07799.5
9.86-80.096.30.05126.241186500.9950.02299.2

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Phasing

PhasingMethod: molecular replacement

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Processing

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

3ebg


Resolution: 1.8→44.284 Å / FOM work R set: 0.885 / SU ML: 0.19 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 18.47 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1937 4562 5.02 %
Rwork0.1591 86362 -
obs0.1609 90924 99.67 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 83.02 Å2 / Biso mean: 22.41 Å2 / Biso min: 7.38 Å2
Refinement stepCycle: final / Resolution: 1.8→44.284 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7204 0 28 888 8120
Biso mean--17.8 32.33 -
Num. residues----889
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077479
X-RAY DIFFRACTIONf_angle_d1.01410150
X-RAY DIFFRACTIONf_chiral_restr0.0411123
X-RAY DIFFRACTIONf_plane_restr0.0051297
X-RAY DIFFRACTIONf_dihedral_angle_d13.1322795
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 (%)
1.8-1.82050.28551300.26352841297199
1.8205-1.84190.25711240.2452880300499
1.8419-1.86430.26041570.22462797295499
1.8643-1.88790.24551420.217728542996100
1.8879-1.91280.29951490.22052808295799
1.9128-1.9390.26231540.217928633017100
1.939-1.96670.24021510.18782831298299
1.9667-1.9960.2271460.17722838298499
1.996-2.02720.21571480.171428533001100
2.0272-2.06050.20421620.17282853301599
2.0605-2.0960.2131710.173728162987100
2.096-2.13410.18891680.16062822299099
2.1341-2.17520.22121550.158928693024100
2.1752-2.21960.20751570.160328603017100
2.2196-2.26780.21451290.173328622991100
2.2678-2.32060.21681560.162828593015100
2.3206-2.37860.20741520.16328893041100
2.3786-2.44290.20721420.156528723014100
2.4429-2.51480.22381600.159228583018100
2.5148-2.59590.19171570.156529043061100
2.5959-2.68870.1911510.163328623013100
2.6887-2.79630.20721470.165928923039100
2.7963-2.92360.21051720.162728973069100
2.9236-3.07770.20351570.159728773034100
3.0777-3.27050.18611390.155629203059100
3.2705-3.52290.18181400.145529313071100
3.5229-3.87720.14031510.133829493100100
3.8772-4.43780.16131550.123929493104100
4.4378-5.58940.14461550.125629613116100
5.5894-44.29770.1681850.155430953280100
Refinement TLS params.Method: refined / Origin x: 17.8972 Å / Origin y: 3.9006 Å / Origin z: 10.1894 Å
111213212223313233
T0.0861 Å2-0.005 Å20.0098 Å2-0.1058 Å20.0089 Å2--0.0942 Å2
L0.3503 °2-0.1105 °20.0557 °2-0.732 °20.1939 °2--0.6344 °2
S-0.0451 Å °-0.0246 Å °0.0481 Å °-0.0016 Å °0.0171 Å °-0.0144 Å °-0.0667 Å °-0.0056 Å °0.0258 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA196 - 1084
2X-RAY DIFFRACTION1allB1 - 2
3X-RAY DIFFRACTION1allC1 - 910
4X-RAY DIFFRACTION1allD1 - 2

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