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- PDB-8ewz: Plasmodium falciparum M1 in complex with inhibitor 9c -

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Basic information

Entry
Database: PDB / ID: 8ewz
TitlePlasmodium falciparum M1 in complex with inhibitor 9c
ComponentsM1 family aminopeptidase
KeywordsHYDROLASE/HYDROLASE inhibitor / Malaria / metalloaminopeptidase / inhibitor complex / HYDROLASE / 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
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 / Peptidase M1, alanine aminopeptidase/leukotriene A4 hydrolase / Peptidase M1, membrane alanine aminopeptidase / Aminopeptidase N-like , N-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 / 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 / Peptidase M4/M1, CTD superfamily / Neutral zinc metallopeptidases, zinc-binding region signature.
Similarity search - Domain/homology
Chem-X0I / Aminopeptidase N
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsCalic, P.P.S. / McGowan, S. / Webb, C.T.
Funding support Australia, 1items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)1185354 Australia
CitationJournal: Eur.J.Med.Chem. / Year: 2022
Title: Structure-based development of potent Plasmodium falciparum M1 and M17 aminopeptidase selective and dual inhibitors via S1'-region optimisation.
Authors: Calic, P.P.S. / Vinh, N.B. / Webb, C.T. / Malcolm, T.R. / Ngo, A. / Lowes, K. / Drinkwater, N. / McGowan, S. / Scammells, P.J.
History
DepositionOct 24, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 18, 2023Provider: repository / Type: Initial release
Revision 1.1Jan 25, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)105,85012
Polymers104,8341
Non-polymers1,01711
Water20,5371140
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, 108.780, 117.480
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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Protein , 1 types, 1 molecules A

#1: Protein M1 family aminopeptidase / Pfa-M1


Mass: 104833.969 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Production host: Escherichia coli (E. coli)
References: UniProt: O96935, Hydrolases; Acting on peptide bonds (peptidases); Aminopeptidases

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Non-polymers , 6 types, 1151 molecules

#2: Chemical ChemComp-X0I / (2R)-2-(cyclopentylcarbamamido)-N-hydroxy-2-(3',4',5'-trifluoro[1,1'-biphenyl]-4-yl)acetamide


Mass: 407.386 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H20F3N3O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


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


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-ZN / ZINC ION


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


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1140 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.31 Å3/Da / Density % sol: 46.78 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 20-30% poly(ethylene glycol) (PEG)8000, 0.1 M Tris pH 7.5-8.5, 0.2 M MgCl2, 10% glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX1 / Wavelength: 0.9537 Å
DetectorType: ADSC QUANTUM 210r / Detector: CCD / Date: Jul 13, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 1.75→46.44 Å / Num. obs: 98459 / % possible obs: 99.97 % / Redundancy: 2 % / Biso Wilson estimate: 16.01 Å2 / CC1/2: 0.997 / CC star: 0.999 / Rmerge(I) obs: 0.03999 / Net I/σ(I): 9.79
Reflection shellResolution: 1.75→1.813 Å / Num. unique obs: 9736 / CC1/2: 0.884

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
iMOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3EBG

3ebg


Resolution: 1.75→46.44 Å / SU ML: 0.1833 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 17.4984
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1867 4927 5.01 %
Rwork0.157 93513 -
obs0.1585 98440 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 18.63 Å2
Refinement stepCycle: LAST / Resolution: 1.75→46.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7222 0 62 1140 8424
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00637556
X-RAY DIFFRACTIONf_angle_d0.806210250
X-RAY DIFFRACTIONf_chiral_restr0.0521131
X-RAY DIFFRACTIONf_plane_restr0.00671307
X-RAY DIFFRACTIONf_dihedral_angle_d13.96132842
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.75-1.770.2851590.24773068X-RAY DIFFRACTION100
1.77-1.790.25891560.23623078X-RAY DIFFRACTION100
1.79-1.810.2831500.22153125X-RAY DIFFRACTION100
1.81-1.840.23471280.19783088X-RAY DIFFRACTION100
1.84-1.860.22021720.19293077X-RAY DIFFRACTION100
1.86-1.890.2281580.18073108X-RAY DIFFRACTION100
1.89-1.910.2051560.17463068X-RAY DIFFRACTION99.97
1.91-1.940.2151750.16813074X-RAY DIFFRACTION100
1.94-1.970.21531600.16323101X-RAY DIFFRACTION100
1.97-20.19021600.16193103X-RAY DIFFRACTION100
2-2.040.18881590.1633067X-RAY DIFFRACTION100
2.04-2.070.19491790.16443074X-RAY DIFFRACTION99.97
2.07-2.110.17421890.15753084X-RAY DIFFRACTION100
2.11-2.160.18951700.15963090X-RAY DIFFRACTION99.94
2.16-2.20.19811740.15433076X-RAY DIFFRACTION99.97
2.2-2.260.18281400.15053134X-RAY DIFFRACTION99.97
2.26-2.310.22421670.16253080X-RAY DIFFRACTION99.97
2.31-2.380.20171680.16373134X-RAY DIFFRACTION99.97
2.38-2.440.20821500.15553107X-RAY DIFFRACTION100
2.44-2.520.19981760.15593106X-RAY DIFFRACTION99.91
2.52-2.610.20021740.15973099X-RAY DIFFRACTION99.91
2.61-2.720.181590.15823132X-RAY DIFFRACTION100
2.72-2.840.18371710.16533106X-RAY DIFFRACTION100
2.84-2.990.20621610.15823123X-RAY DIFFRACTION100
2.99-3.180.20461620.15583147X-RAY DIFFRACTION100
3.18-3.430.17181570.14553171X-RAY DIFFRACTION100
3.43-3.770.14281620.13233173X-RAY DIFFRACTION99.97
3.77-4.310.15041700.13053162X-RAY DIFFRACTION100
4.31-5.430.14631620.12923230X-RAY DIFFRACTION100
5.44-46.440.17472030.16683328X-RAY DIFFRACTION99.8
Refinement TLS params.Method: refined / Origin x: 17.8400045305 Å / Origin y: 112.782936201 Å / Origin z: 10.2733754598 Å
111213212223313233
T0.0742826722078 Å2-0.0107844382292 Å20.00488937401008 Å2-0.0840521846801 Å20.0130527889777 Å2--0.0737317408733 Å2
L0.350419850094 °2-0.110120327609 °20.0111941321426 °2-0.602265253728 °20.11353216698 °2--0.496806685012 °2
S-0.0322968376318 Å °-0.00369734130534 Å °0.0354828540593 Å °-0.00559451081376 Å °0.00601996210651 Å °-0.0149156607253 Å °-0.0329996393257 Å °0.00641558911149 Å °0.0263136322127 Å °
Refinement TLS groupSelection details: all

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