2VXD

The structure of the C-terminal domain of Nucleophosmin


Experimental Data Snapshot

  • Method: SOLUTION NMR
  • Conformers Calculated: 150 
  • Conformers Submitted: 20 
  • Selection Criteria: LEAST RESTRAINT VIOLATION 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Structural Consequences of Nucleophosmin Mutations in Acute Myeloid Leukemia.

Grummitt, C.G.Townsley, F.M.Johnson, C.M.Warren, A.J.Bycroft, M.

(2008) J Biol Chem 283: 23326

  • DOI: https://doi.org/10.1074/jbc.M801706200
  • Primary Citation of Related Structures:  
    2VXD

  • PubMed Abstract: 

    Mutations affecting NPM1 (nucleophosmin) are the most common genetic lesions found in acute myeloid leukemia (AML). NPM1 is one of the most abundant proteins found in the nucleolus and has links to the MDM2/p53 tumor suppressor pathway. A distinctive feature of NPM1 mutants in AML is their aberrant localization to the cytoplasm of leukemic cells. This mutant phenotype is the result of the substitution of several C-terminal residues, including one or two conserved tryptophan residues, with a leucine-rich nuclear export signal. The exact molecular mechanism underlying the loss of nucleolar retention, and the role of the tryptophans, remains unknown. In this study we have determined the structure of an independently folded globular domain in the C terminus of NPM1 using NMR spectroscopy, and we report that the conserved tryptophans are critical for structure. This domain is necessary for the nucleolar targeting of NPM1 and is disrupted by mutations in AML with cytoplasmic NPM1. Furthermore, we identify conserved surface-exposed lysine residues that are functionally rather than structurally important for nucleolar localization. This study provides new focus for efforts to understand the pathogenesis of AML with cytoplasmic NPM1 and may be used to aid the design of small molecules that target the C-terminal domain of NPM1 to act as novel anti-proliferative and anti-leukemia therapeutics.


  • Organizational Affiliation

    Medical Research Council Centre for Protein Engineering, Cambridge CB2 0QH, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
NUCLEOPHOSMIN54Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P06748 (Homo sapiens)
Explore P06748 
Go to UniProtKB:  P06748
PHAROS:  P06748
GTEx:  ENSG00000181163 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP06748
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: SOLUTION NMR
  • Conformers Calculated: 150 
  • Conformers Submitted: 20 
  • Selection Criteria: LEAST RESTRAINT VIOLATION 

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-07-15
    Type: Initial release
  • Version 1.1: 2013-07-24
    Changes: Database references, Derived calculations, Other, Version format compliance
  • Version 1.2: 2021-06-23
    Changes: Data collection, Other
  • Version 1.3: 2024-05-15
    Changes: Data collection, Database references