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- PDB-8dsr: Structure of Plasmepsin X (PM10, PMX) from Plasmodium falciparum ... -

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Basic information

Entry
Database: PDB / ID: 8dsr
TitleStructure of Plasmepsin X (PM10, PMX) from Plasmodium falciparum 3D7 in complex with UCB7362
ComponentsPlasmepsin X
KeywordsHYDROLASE / Plasmepsin X / Plasmodium falciparum / PM10 / PMX
Function / homology
Function and homology information


MHC class II antigen presentation / Neutrophil degranulation / entry into host cell by a symbiont-containing vacuole / Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases / protein autoprocessing / transport vesicle / protein processing / aspartic-type endopeptidase activity / lysosome / proteolysis
Similarity search - Function
Pepsin-like domain / Eukaryotic aspartyl protease / Aspartic peptidase A1 family / Peptidase family A1 domain / Peptidase family A1 domain profile. / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily
Similarity search - Domain/homology
Chem-TWU / Plasmepsin X
Similarity search - Component
Biological speciesPlasmodium falciparum 3D7 (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.85 Å
AuthorsAbendroth, J. / Lorimer, D.D.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery and Characterization of Potent, Efficacious, Orally Available Antimalarial Plasmepsin X Inhibitors and Preclinical Safety Assessment of UCB7362 .
Authors: Lowe, M.A. / Cardenas, A. / Valentin, J.P. / Zhu, Z. / Abendroth, J. / Castro, J.L. / Class, R. / Delaunois, A. / Fleurance, R. / Gerets, H. / Gryshkova, V. / King, L. / Lorimer, D.D. / ...Authors: Lowe, M.A. / Cardenas, A. / Valentin, J.P. / Zhu, Z. / Abendroth, J. / Castro, J.L. / Class, R. / Delaunois, A. / Fleurance, R. / Gerets, H. / Gryshkova, V. / King, L. / Lorimer, D.D. / MacCoss, M. / Rowley, J.H. / Rosseels, M.L. / Royer, L. / Taylor, R.D. / Wong, M. / Zaccheo, O. / Chavan, V.P. / Ghule, G.A. / Tapkir, B.K. / Burrows, J.N. / Duffey, M. / Rottmann, M. / Wittlin, S. / Angulo-Barturen, I. / Jimenez-Diaz, M.B. / Striepen, J. / Fairhurst, K.J. / Yeo, T. / Fidock, D.A. / Cowman, A.F. / Favuzza, P. / Crespo-Fernandez, B. / Gamo, F.J. / Goldberg, D.E. / Soldati-Favre, D. / Laleu, B. / de Haro, T.
History
DepositionJul 22, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 19, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 9, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Jan 25, 2023Group: Other / Structure summary
Category: audit_author / pdbx_SG_project ...audit_author / pdbx_SG_project / pdbx_database_status / struct_keywords
Item: _pdbx_database_status.SG_entry / _struct_keywords.text
Revision 1.3Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.4Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Plasmepsin X
B: Plasmepsin X
hetero molecules


Theoretical massNumber of molelcules
Total (without water)106,4674
Polymers105,5292
Non-polymers9382
Water00
1
A: Plasmepsin X
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,2332
Polymers52,7651
Non-polymers4691
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Plasmepsin X
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,2332
Polymers52,7651
Non-polymers4691
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)54.710, 61.430, 143.980
Angle α, β, γ (deg.)90.000, 90.769, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and (resid 232 through 287 or (resid 288...
d_2ens_1(chain "B" and (resid 232 through 299 or (resid 300...

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1LYSLYSA1 - 332
d_12ens_1382382B
d_21ens_1LYSLYSC1 - 332
d_22ens_1382382D

NCS oper: (Code: givenMatrix: (0.978551022, -0.0533473445209, -0.198977280552), (-0.0489741413555, -0.998439377323, 0.0268392117709), (-0.200098552773, -0.0165187966437, -0.979636513476)Vector: -12. ...NCS oper: (Code: given
Matrix: (0.978551022, -0.0533473445209, -0.198977280552), (-0.0489741413555, -0.998439377323, 0.0268392117709), (-0.200098552773, -0.0165187966437, -0.979636513476)
Vector: -12.0014292831, -8.45377426635, 70.3316104242)

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Components

#1: Protein Plasmepsin X / PfPMX / Plasmepsin 10


Mass: 52764.504 Da / Num. of mol.: 2 / Fragment: PlfaA.17789.b.HE11
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Strain: isolate 3D7 / Gene: PMX, PF3D7_0808200 / Plasmid: PlfaA.17789.b.HE11 / Production host: Homo sapiens (human) / Strain (production host): HEK
References: UniProt: Q8IAS0, Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases
#2: Chemical ChemComp-TWU / (2E,6S)-6-{2-chloro-3-[(2-cyclopropylpyrimidin-5-yl)amino]phenyl}-2-imino-6-methyl-3-[(2S,4S)-2-methyloxan-4-yl]-1,3-diazinan-4-one


Mass: 468.979 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H29ClN6O2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
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: 2.31 Å3/Da / Density % sol: 46.9 %
Crystal growTemperature: 290 K / Method: vapor diffusion, sitting drop / pH: 9.4
Details: RigakuReagents JCSG A7 optimization screen: 100mM Tris HCl / NaOH pH 9.4, 17.86% PEG 8000: PlfaA.17789.b.HE11.PD38363 at 11.4mg/ml: cryo: 20% EG: tray: 3908603 D3: puck qpu2-2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Apr 18, 2019
RadiationMonochromator: C111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 2.85→50 Å / Num. obs: 22559 / % possible obs: 99.6 % / Redundancy: 3.683 % / Biso Wilson estimate: 68.75 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.069 / Rrim(I) all: 0.082 / Χ2: 0.915 / Net I/σ(I): 12.66
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
2.85-2.923.7970.5622.1116850.9130.65699.8
2.92-33.7940.42.8615810.9490.46799.7
3-3.093.7960.363.1815600.9510.4299.9
3.09-3.193.8090.2794.1915460.9690.326100
3.19-3.293.7880.2045.5114700.9840.23899.7
3.29-3.413.7730.1636.7814530.9880.19199.9
3.41-3.543.7250.1378.1113380.9920.16199.8
3.54-3.683.6180.137913430.9870.16298.7
3.68-3.843.5970.11310.9912740.9890.13398.7
3.84-4.033.6240.07814.2512070.9940.09299.4
4.03-4.253.6610.05817.8511720.9970.06899.9
4.25-4.513.6160.0521.611080.9970.05999.6
4.51-4.823.6110.04623.1110460.9970.05499.8
4.82-5.23.6010.04424.389700.9960.052100
5.2-5.73.630.04423.88930.9970.05199.8
5.7-6.373.6190.04223.978210.9970.0599.9
6.37-7.363.550.03925.67240.9970.046100
7.36-9.013.5340.03529.526260.9970.04299.5
9.01-12.753.4310.0331.714730.9980.03599.4
12.75-503.1190.0330.942690.9970.03694.4

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
PHENIX1.19 dev 4035refinement
PDB_EXTRACT3.27data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: apo structure 7ry7, minus pro domain

7ry7


Resolution: 2.85→47.99 Å / SU ML: 0.4296 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 34.1224
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflectionSelection details
Rfree0.28 2027 9.01 %0
Rwork0.2344 20468 --
obs0.2385 22495 99.38 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 78.08 Å2
Refinement stepCycle: LAST / Resolution: 2.85→47.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4989 0 66 0 5055
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00265187
X-RAY DIFFRACTIONf_angle_d0.56737080
X-RAY DIFFRACTIONf_chiral_restr0.0486806
X-RAY DIFFRACTIONf_plane_restr0.004904
X-RAY DIFFRACTIONf_dihedral_angle_d13.55711766
Refine LS restraints NCSType: Torsion NCS / Rms dev position: 0.619444188874 Å
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.85-2.920.42421500.37071449X-RAY DIFFRACTION99.32
2.92-30.34191150.32071462X-RAY DIFFRACTION99.24
3-3.090.4231450.29561428X-RAY DIFFRACTION99.31
3.09-3.190.33061630.28241448X-RAY DIFFRACTION99.57
3.19-3.30.27521540.26951438X-RAY DIFFRACTION99.38
3.3-3.430.34931580.28191478X-RAY DIFFRACTION99.45
3.43-3.590.33891280.28661441X-RAY DIFFRACTION99.43
3.59-3.780.33541500.30611403X-RAY DIFFRACTION98.04
3.78-4.020.29261360.22741474X-RAY DIFFRACTION99.51
4.02-4.330.21561310.20371492X-RAY DIFFRACTION99.69
4.33-4.760.21471640.16741452X-RAY DIFFRACTION99.63
4.76-5.450.23091550.18281478X-RAY DIFFRACTION99.88
5.45-6.860.31511290.23631514X-RAY DIFFRACTION99.88
6.86-47.990.25781490.21881511X-RAY DIFFRACTION98.99
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)
12.412847278362.10096097481-2.734803561882.44887521172-2.499806603134.484383066280.283637162507-0.311301609420.1330744036760.237185966066-0.2624859839640.0669451371446-0.654405948946-0.391274873270.1072410059930.677963746442-0.03013568705790.06404647143210.522699315943-0.02641240616430.549549856427-10.50065570895.9043578778356.8551114408
24.174130160540.0064563448313.64750229263.82060472354-1.200069344263.696731678610.192486985538-0.518920943104-0.3056823192920.3016600859380.3140422599010.7165317659410.709797072713-1.09034782861-0.403758772930.641110535501-0.01950403797350.01472270359180.7115977902140.002346163381790.522310868064-18.3144750034-4.7816299984349.427771773
33.988155309990.004391454941621.056592904051.85283074547-0.4175949780524.427380983740.05959231943730.349558046632-0.141296206437-0.269973070484-0.0805619815234-0.008195031741960.06202417472960.09843769588240.08332528615230.3829149759050.0007262873014770.1042012968640.326224920028-0.02888107423120.380471867597-0.50194613159-2.0910854832854.5841458962
41.817918058070.308483448504-0.5306644946914.71198566217-4.388043955127.164132225890.0401143249199-0.0646645309083-0.1787221398580.0988318424452-0.286251988952-0.3628485962830.1631660894970.4483544815920.224321738210.3093752563310.0331057500343-0.0021924034460.351636039243-0.008792232711430.5552696334828.59373016009-5.9612828630768.5393895225
55.24058842314-3.253712774014.230345647893.5799576455-2.564765934114.668131349490.698308453596-0.0355673428506-0.289198053495-0.395544202625-0.4030336750660.01632752413690.412839331345-0.6519014225360.2991358424690.829108314182-0.1630616033180.01630682274560.657733054229-0.09903962880730.490810278828-33.932455142-12.293836115716.6160612764
63.47002915173-0.692399812605-0.9096782904512.40408437057-0.003288594158937.14615434001-0.05410096470570.003149599816360.259604089911-0.02731026561020.04803452639840.108332034853-0.128599738443-0.241142082065-0.03903407047680.507320718006-0.0272419395572-0.08051741838630.517637895948-0.03035939659210.407119443288-26.4808687067-2.9751355441818.2338577859
73.50766437102-2.528774317461.305154152315.8971024946-2.578976130965.158283642770.1831783128930.06755735152760.135067096123-0.739616118822-0.272092792826-0.503062381580.1382373900370.797622910155-0.01146091174910.625596413547-0.06547390504520.1104456650690.6919841082320.01111190562540.551335893829-17.256743125-2.420944658072.41968360506
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 232 through 258 )AA232 - 2581 - 27
22chain 'A' and (resid 259 through 306 )AA259 - 30628 - 75
33chain 'A' and (resid 307 through 466 )AA307 - 46676 - 228
44chain 'A' and (resid 467 through 570 )AA467 - 570229 - 332
55chain 'B' and (resid 232 through 258 )BC232 - 2581 - 27
66chain 'B' and (resid 259 through 476 )BC259 - 47628 - 238
77chain 'B' and (resid 477 through 570 )BC477 - 570239 - 332

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