5ZC9

Crystal structure of the human eIF4A1-ATP analog-RocA-polypurine RNA complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.195 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

The Translation Inhibitor Rocaglamide Targets a Bimolecular Cavity between eIF4A and Polypurine RNA.

Iwasaki, S.Iwasaki, W.Takahashi, M.Sakamoto, A.Watanabe, C.Shichino, Y.Floor, S.N.Fujiwara, K.Mito, M.Dodo, K.Sodeoka, M.Imataka, H.Honma, T.Fukuzawa, K.Ito, T.Ingolia, N.T.

(2019) Mol Cell 73: 738

  • DOI: https://doi.org/10.1016/j.molcel.2018.11.026
  • Primary Citation of Related Structures:  
    5ZC9

  • PubMed Abstract: 

    A class of translation inhibitors, exemplified by the natural product rocaglamide A (RocA), isolated from Aglaia genus plants, exhibits antitumor activity by clamping eukaryotic translation initiation factor 4A (eIF4A) onto polypurine sequences in mRNAs. This unusual inhibitory mechanism raises the question of how the drug imposes sequence selectivity onto a general translation factor. Here, we determined the crystal structure of the human eIF4A1⋅ATP analog⋅RocA⋅polypurine RNA complex. RocA targets the "bi-molecular cavity" formed characteristically by eIF4A1 and a sharply bent pair of consecutive purines in the RNA. Natural amino acid substitutions found in Aglaia eIF4As changed the cavity shape, leading to RocA resistance. This study provides an example of an RNA-sequence-selective interfacial inhibitor fitting into the space shaped cooperatively by protein and RNA with specific sequences.


  • Organizational Affiliation

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; RNA Systems Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 277-8561, Japan. Electronic address: shintaro.iwasaki@riken.jp.


Macromolecules

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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Eukaryotic initiation factor 4A-I394Homo sapiensMutation(s): 0 
Gene Names: EIF4A1DDX2AEIF4A
EC: 3.6.4.13
UniProt & NIH Common Fund Data Resources
Find proteins for P60842 (Homo sapiens)
Explore P60842 
Go to UniProtKB:  P60842
PHAROS:  P60842
GTEx:  ENSG00000161960 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP60842
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains LengthOrganismImage
RNA (5'-R(*AP*GP*AP*GP*AP*GP*AP*GP*AP*G)-3')10synthetic construct
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ANP
Query on ANP

Download Ideal Coordinates CCD File 
C [auth A]PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER
C10 H17 N6 O12 P3
PVKSNHVPLWYQGJ-KQYNXXCUSA-N
RCG
Query on RCG

Download Ideal Coordinates CCD File 
E [auth B](1R,2R,3S,3aR,8bS)-6,8-dimethoxy-3a-(4-methoxyphenyl)-N,N-dimethyl-1,8b-bis(oxidanyl)-3-phenyl-2,3-dihydro-1H-cyclopenta[b][1]benzofuran-2-carboxamide
C29 H31 N O7
DAPAQENNNINUPW-IDAMAFBJSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
D [auth A]MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.195 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 68.508α = 90
b = 100.263β = 90
c = 155.422γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-01-16
    Type: Initial release
  • Version 1.1: 2019-03-13
    Changes: Data collection, Database references
  • Version 1.2: 2023-11-22
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary