6AZ3

Cryo-EM structure of of the large subunit of Leishmania ribosome bound to paromomycin


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 2.50 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Atomic resolution snapshot of Leishmania ribosome inhibition by the aminoglycoside paromomycin.

Shalev-Benami, M.Zhang, Y.Rozenberg, H.Nobe, Y.Taoka, M.Matzov, D.Zimmerman, E.Bashan, A.Isobe, T.Jaffe, C.L.Yonath, A.Skiniotis, G.

(2017) Nat Commun 8: 1589-1589

  • DOI: 10.1038/s41467-017-01664-4
  • Primary Citation of Related Structures:  
    6AZ1, 6AZ3

  • PubMed Abstract: 
  • Leishmania is a single-celled eukaryotic parasite afflicting millions of humans worldwide, with current therapies limited to a poor selection of drugs that mostly target elements in the parasite's cell envelope. Here we determined the atomic resolution electron cryo-microscopy (cryo-EM) structure of the Leishmania ribosome in complex with paromomycin (PAR), a highly potent compound recently approved for treatment of the fatal visceral leishmaniasis (VL) ...

    Leishmania is a single-celled eukaryotic parasite afflicting millions of humans worldwide, with current therapies limited to a poor selection of drugs that mostly target elements in the parasite's cell envelope. Here we determined the atomic resolution electron cryo-microscopy (cryo-EM) structure of the Leishmania ribosome in complex with paromomycin (PAR), a highly potent compound recently approved for treatment of the fatal visceral leishmaniasis (VL). The structure reveals the mechanism by which the drug induces its deleterious effects on the parasite. We further show that PAR interferes with several aspects of cytosolic translation, thus highlighting the cytosolic rather than the mitochondrial ribosome as the primary drug target. The results also highlight unique as well as conserved elements in the PAR-binding pocket that can serve as hotspots for the development of novel therapeutics.


    Organizational Affiliation

    Departments of Molecular and Cellular Physiology, and Structural Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA. yiorgo@stanford.edu.



Macromolecules

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Entity ID: 1
MoleculeChainsSequence LengthOrganismDetailsImage
ribosomal protein uL2 A254Leishmania donovaniMutation(s): 0 
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Entity ID: 2
MoleculeChainsSequence LengthOrganismDetailsImage
ribosomal protein uL3 B402Leishmania donovaniMutation(s): 0 
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Entity ID: 3
MoleculeChainsSequence LengthOrganismDetailsImage
ribosomal protein uL4 C366Leishmania donovaniMutation(s): 0 
Find proteins for E9BKR3 (Leishmania donovani (strain BPK282A1))
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Entity ID: 4
MoleculeChainsSequence LengthOrganismDetailsImage
ribosomal protein uL5 D168Leishmania donovaniMutation(s): 0 
Find proteins for E9BFL1 (Leishmania donovani (strain BPK282A1))
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Entity ID: 5
MoleculeChainsSequence LengthOrganismDetailsImage
ribosomal protein uL6 E186Leishmania donovaniMutation(s): 0 
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Entity ID: 6
MoleculeChainsSequence LengthOrganismDetailsImage
ribosomal protein eL6 F195Leishmania donovaniMutation(s): 0 
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Entity ID: 7
MoleculeChainsSequence LengthOrganismDetailsImage
ribosomal protein eL8 G348Leishmania donovaniMutation(s): 0 
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Entity ID: 8
MoleculeChainsSequence LengthOrganismDetailsImage
ribosomal protein uL13 H221Leishmania donovaniMutation(s): 0 
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Entity ID: 9
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ribosomal protein eL13 I212Leishmania donovaniMutation(s): 0 
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Entity ID: 10
MoleculeChainsSequence LengthOrganismDetailsImage
ribosomal protein uL14 J134Leishmania donovaniMutation(s): 0 
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Entity ID: 11
MoleculeChainsSequence LengthOrganismDetailsImage
ribosomal protein eL14 K149Leishmania donovaniMutation(s): 0 
Gene Names: RPL14LPD23
Find proteins for Q25278 (Leishmania donovani)
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Entity ID: 12
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ribosomal protein uL15 L144Leishmania donovaniMutation(s): 0 
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Entity ID: 13
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ribosomal protein eL15 M203Leishmania donovaniMutation(s): 0 
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Entity ID: 14
MoleculeChainsSequence LengthOrganismDetailsImage
ribosomal protein uL16 N213Leishmania donovaniMutation(s): 0 
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Entity ID: 15
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ribosomal protein uL18 O305Leishmania donovaniMutation(s): 0 
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Entity ID: 16
MoleculeChainsSequence LengthOrganismDetailsImage
ribosomal protein eL18 P197Leishmania donovaniMutation(s): 0 
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Entity ID: 17
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ribosomal protein eL19 Q189Leishmania donovaniMutation(s): 0 
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Entity ID: 18
MoleculeChainsSequence LengthOrganismDetailsImage
ribosomal protein eL20 R178Leishmania donovaniMutation(s): 0 
Find proteins for E9BRT7 (Leishmania donovani (strain BPK282A1))
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Entity ID: 19
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ribosomal protein eL21 S154Leishmania donovaniMutation(s): 0 
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Entity ID: 20
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ribosomal protein uL22 T154Leishmania donovaniMutation(s): 0 
Find proteins for E9BGL6 (Leishmania donovani (strain BPK282A1))
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Entity ID: 21
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ribosomal protein eL22 U121Leishmania donovaniMutation(s): 0 
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Entity ID: 22
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ribosomal protein uL23 V118Leishmania donovaniMutation(s): 0 
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Entity ID: 23
MoleculeChainsSequence LengthOrganismDetailsImage
ribosomal protein uL24 W121Leishmania donovaniMutation(s): 0 
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Entity ID: 24
MoleculeChainsSequence LengthOrganismDetailsImage
ribosomal protein eL24 X65Leishmania donovaniMutation(s): 0 
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Entity ID: 25
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ribosomal protein eL27 Y132Leishmania donovaniMutation(s): 0 
Find proteins for E9BP34 (Leishmania donovani (strain BPK282A1))
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Entity ID: 26
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ribosomal protein eL28 Z140Leishmania donovaniMutation(s): 0 
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Entity ID: 27
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ribosomal protein uL29 a125Leishmania donovaniMutation(s): 0 
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Entity ID: 28
MoleculeChainsSequence LengthOrganismDetailsImage
ribosomal protein eL29 b68Leishmania donovaniMutation(s): 0 
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Entity ID: 29
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ribosomal protein uL30 c227Leishmania donovaniMutation(s): 0 
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Entity ID: 30
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ribosomal protein eL30 d92Leishmania donovaniMutation(s): 0 
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Entity ID: 31
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ribosomal protein eL31 e119Leishmania donovaniMutation(s): 0 
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Entity ID: 32
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ribosomal protein eL32 f130Leishmania donovaniMutation(s): 0 
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Entity ID: 33
MoleculeChainsSequence LengthOrganismDetailsImage
ribosomal protein eL33 g125Leishmania donovaniMutation(s): 0 
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Entity ID: 34
MoleculeChainsSequence LengthOrganismDetailsImage
ribosomal protein eL34 h125Leishmania donovaniMutation(s): 0 
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Entity ID: 35
MoleculeChainsSequence LengthOrganismDetailsImage
ribosomal protein eL36 i97Leishmania donovaniMutation(s): 0 
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Entity ID: 36
MoleculeChainsSequence LengthOrganismDetailsImage
ribosomal protein eL37 j80Leishmania donovaniMutation(s): 0 
Gene Names: RPL37
Find proteins for P62885 (Leishmania donovani)
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Entity ID: 37
MoleculeChainsSequence LengthOrganismDetailsImage
ribosomal protein eL38 k76Leishmania donovaniMutation(s): 0 
Find proteins for E9B7P2 (Leishmania donovani (strain BPK282A1))
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Entity ID: 38
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ribosomal protein eL39 l50Leishmania donovaniMutation(s): 0 
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Entity ID: 39
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ribosomal protein eL40 m50Leishmania donovaniMutation(s): 0 
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Entity ID: 40
MoleculeChainsSequence LengthOrganismDetailsImage
ribosomal protein eL41 n33Leishmania donovaniMutation(s): 0 
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Entity ID: 41
MoleculeChainsSequence LengthOrganismDetailsImage
ribosomal protein eL43 o90Leishmania donovaniMutation(s): 0 
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Entity ID: 42
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ribosomal protein eL44 p96Leishmania donovaniMutation(s): 0 
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Entity ID: 43
MoleculeChainsLengthOrganismImage
rRNA alpha11778Leishmania donovani
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Entity ID: 44
MoleculeChainsLengthOrganismImage
rRNA beta21526Leishmania donovani
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Entity ID: 45
MoleculeChainsLengthOrganismImage
rRNA gamma3211Leishmania donovani
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Entity ID: 46
MoleculeChainsLengthOrganismImage
rRNA delta4183Leishmania donovani
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Entity ID: 47
MoleculeChainsLengthOrganismImage
rRNA epsilon5133Leishmania donovani
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Entity ID: 48
MoleculeChainsLengthOrganismImage
rRNA zeta671Leishmania donovani
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Entity ID: 49
MoleculeChainsLengthOrganismImage
rRNA 5.8S7171Leishmania donovani
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Entity ID: 50
MoleculeChainsLengthOrganismImage
rRNA 5S8118Leishmania donovani
Small Molecules
Ligands 3 Unique
IDChainsName / Formula / InChI Key2D Diagram3D Interactions
PAR
Query on PAR

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1, 2, 7
PAROMOMYCIN
C23 H45 N5 O14
UOZODPSAJZTQNH-LSWIJEOBSA-N
 Ligand Interaction
C
Query on C

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2
CYTIDINE-5'-MONOPHOSPHATE
C9 H14 N3 O8 P
IERHLVCPSMICTF-XVFCMESISA-N
 Ligand Interaction
MG
Query on MG

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1, 2, 3, 4, 5, 7
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
 Ligand Interaction
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 2.50 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-12-06
    Type: Initial release
  • Version 1.1: 2017-12-13
    Changes: Database references