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- PDB-6wnk: Macrocyclic peptides TDI5575 that selectively inhibit the Mycobac... -

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Basic information

Entry
Database: PDB / ID: 6wnk
TitleMacrocyclic peptides TDI5575 that selectively inhibit the Mycobacterium tuberculosis proteasome
Components(Proteasome subunit ...) x 2
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Mycobacterium tuberculosis / proteasome inhibitor / Macrocyclic peptides / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


proteasome endopeptidase complex / proteasome core complex, beta-subunit complex / threonine-type endopeptidase activity / proteasome core complex, alpha-subunit complex / proteasomal protein catabolic process / modification-dependent protein catabolic process / cytoplasm
Similarity search - Function
Proteasome, alpha subunit, bacterial / Proteasome subunit beta, actinobacteria / Proteasome B-type subunit / Proteasome beta-type subunit profile. / : / Proteasome alpha-type subunit / Proteasome alpha-type subunit profile. / Proteasome subunit / Proteasome, subunit alpha/beta / Nucleophile aminohydrolases, N-terminal
Similarity search - Domain/homology
Macrocyclic peptide TDI5575 / CITRIC ACID / DIMETHYLFORMAMIDE / Chem-U5Y / Proteasome subunit alpha / Proteasome subunit beta
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.28 Å
AuthorsHsu, H.C. / Li, H.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01 AI070285 United States
CitationJournal: J.Med.Chem. / Year: 2021
Title: Macrocyclic Peptides that Selectively Inhibit the Mycobacterium tuberculosis Proteasome.
Authors: Zhang, H. / Hsu, H.C. / Kahne, S.C. / Hara, R. / Zhan, W. / Jiang, X. / Burns-Huang, K. / Ouellette, T. / Imaeda, T. / Okamoto, R. / Kawasaki, M. / Michino, M. / Wong, T.T. / Toita, A. / ...Authors: Zhang, H. / Hsu, H.C. / Kahne, S.C. / Hara, R. / Zhan, W. / Jiang, X. / Burns-Huang, K. / Ouellette, T. / Imaeda, T. / Okamoto, R. / Kawasaki, M. / Michino, M. / Wong, T.T. / Toita, A. / Yukawa, T. / Moraca, F. / Vendome, J. / Saha, P. / Sato, K. / Aso, K. / Ginn, J. / Meinke, P.T. / Foley, M. / Nathan, C.F. / Darwin, K.H. / Li, H. / Lin, G.
History
DepositionApr 22, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 28, 2021Provider: repository / Type: Initial release
Revision 1.1May 19, 2021Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2May 26, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Proteasome subunit alpha
B: Proteasome subunit alpha
C: Proteasome subunit alpha
D: Proteasome subunit alpha
E: Proteasome subunit alpha
F: Proteasome subunit alpha
G: Proteasome subunit alpha
H: Proteasome subunit beta
I: Proteasome subunit beta
J: Proteasome subunit beta
K: Proteasome subunit beta
L: Proteasome subunit beta
M: Proteasome subunit beta
N: Proteasome subunit beta
O: Proteasome subunit alpha
P: Proteasome subunit alpha
Q: Proteasome subunit alpha
R: Proteasome subunit alpha
S: Proteasome subunit alpha
T: Proteasome subunit alpha
U: Proteasome subunit alpha
V: Proteasome subunit beta
W: Proteasome subunit beta
X: Proteasome subunit beta
Y: Proteasome subunit beta
Z: Proteasome subunit beta
a: Proteasome subunit beta
b: Proteasome subunit beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)730,00064
Polymers717,44728
Non-polymers12,55336
Water21,1861176
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area91200 Å2
ΔGint-58 kcal/mol
Surface area218750 Å2
MethodPISA
Unit cell
Length a, b, c (Å)155.635, 115.949, 208.113
Angle α, β, γ (deg.)90.000, 91.580, 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

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Components

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Proteasome subunit ... , 2 types, 28 molecules ABCDEFGOPQRSTUHIJKLMNVWXYZab

#1: Protein
Proteasome subunit alpha / 20S proteasome alpha subunit / Proteasome core protein PrcA


Mass: 25971.975 Da / Num. of mol.: 14
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (bacteria) / Gene: prcA, MRA_2124 / Plasmid: pACYCDuet / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: A5U4D5, proteasome endopeptidase complex
#2: Protein
Proteasome subunit beta / 20S proteasome beta subunit / Proteasome core protein PrcB


Mass: 25274.264 Da / Num. of mol.: 14
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (bacteria) / Gene: prcB, MRA_2125 / Plasmid: PACYCDuet / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: A5U4D6, proteasome endopeptidase complex

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Non-polymers , 4 types, 1212 molecules

#3: Chemical
ChemComp-U5Y / (12S,15S)-N-[(2-fluorophenyl)methyl]-10,13-dioxo-12-{2-oxo-2-[(2R)-2-phenylpyrrolidin-1-yl]ethyl}-2-oxa-11,14-diazatricyclo[15.2.2.1~3,7~]docosa-1(19),3(22),4,6,17,20-hexaene-15-carboxamide


Type: Cyclic peptide / Class: Inhibitor / Mass: 662.749 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: C39H39FN4O5 / Feature type: SUBJECT OF INVESTIGATION / References: Macrocyclic peptide TDI5575
#4: Chemical
ChemComp-CIT / CITRIC ACID


Mass: 192.124 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: C6H8O7
#5: Chemical
ChemComp-DMF / DIMETHYLFORMAMIDE


Mass: 73.094 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C3H7NO
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1176 / 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: 2.62 Å3/Da / Density % sol: 52.99 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.2 / Details: 60mM sodium citrate (pH 6.2), 15% PEG-3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.07812 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Apr 14, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.07812 Å / Relative weight: 1
ReflectionResolution: 2.28→92.97 Å / Num. obs: 332027 / % possible obs: 98.2 % / Redundancy: 7 % / Biso Wilson estimate: 42.06 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.11 / Net I/σ(I): 10.7
Reflection shellResolution: 2.28→2.4 Å / Redundancy: 7.2 % / Rmerge(I) obs: 0.85 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 48823 / CC1/2: 0.724 / % possible all: 99.2

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Processing

Software
NameVersionClassification
Coot1.17.1_3660model building
PHENIX1.17.1_3660refinement
iMOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5TRG

5trg


Resolution: 2.28→87.59 Å / Cross valid method: FREE R-VALUE
RfactorNum. reflection% reflection
Rfree0.2381 16401 4.94 %
Rwork0.1996 --
obs0.2015 331867 98.08 %
Displacement parametersBiso mean: 53.04 Å2
Refinement stepCycle: LAST / Resolution: 2.28→87.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms46316 0 908 1176 48400
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002847947
X-RAY DIFFRACTIONf_angle_d0.599364895
X-RAY DIFFRACTIONf_chiral_restr0.04377293
X-RAY DIFFRACTIONf_plane_restr0.00398540
X-RAY DIFFRACTIONf_dihedral_angle_d24.449217380

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