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PDBsum entry 2vxd

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protein links
Nuclear protein PDB id
2vxd
Jmol
Contents
Protein chain
54 a.a. *
* Residue conservation analysis
PDB id:
2vxd
Name: Nuclear protein
Title: The structure of thE C-terminal domain of nucleophosmin
Structure: Nucleophosmin. Chain: a. Fragment: c-terminal domain, residues 214-265. Synonym: npm, nucleolar phosphoprotein b23, numatrin, nucleolar protein no38. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
NMR struc: 20 models
Authors: M.Bycroft,C.G.Grummitt
Key ref:
C.G.Grummitt et al. (2008). Structural consequences of nucleophosmin mutations in acute myeloid leukemia. J Biol Chem, 283, 23326-23332. PubMed id: 18511415 DOI: 10.1074/jbc.M801706200
Date:
03-Jul-08     Release date:   15-Jul-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P06748  (NPM_HUMAN) -  Nucleophosmin
Seq:
Struc:
294 a.a.
54 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biochemical function     nucleic acid binding     1 term  

 

 
DOI no: 10.1074/jbc.M801706200 J Biol Chem 283:23326-23332 (2008)
PubMed id: 18511415  
 
 
Structural consequences of nucleophosmin mutations in acute myeloid leukemia.
C.G.Grummitt, F.M.Townsley, C.M.Johnson, A.J.Warren, M.Bycroft.
 
  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.
 
  Selected figure(s)  
 
Figure 1.
FIGURE 1. Solution structure of the C-terminal domain of nucleophosmin. A, overlay of the backbone atoms of the 20 lowest energy structures in stereo. B, schematic representation of the lowest energy structure colored blue to red from the N to C terminus (same orientation as in A). Prepared using the program PyMOL (53).
Figure 5.
FIGURE 5. Electrostatic representation of the C-terminal domain showing functionally important residues. The electrostatic surface potential of the C-terminal domain of NPM1 as calculated by the program APBS (56) and colored using a linear color ramp from -20.0 kiloteslas (red) to +20.0 (blue). Lys^263 and Lys^267 are required for nucleolar localization, but Lys^250 is not (see Fig. 6). The natural product avrainvillamide bound to Cys^275 and displaced NPM1 from the nucleolus to the nucleoplasm (45).
 
  The above figures are reprinted from an Open Access publication published by the ASBMB: J Biol Chem (2008, 283, 23326-23332) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21152184 M.S.Lindström (2011).
NPM1/B23: A Multifunctional Chaperone in Ribosome Biogenesis and Chromatin Remodeling.
  Biochem Res Int, 2011, 195209.  
20194897 A.Narla, and B.L.Ebert (2010).
Ribosomopathies: human disorders of ribosome dysfunction.
  Blood, 115, 3196-3205.  
20212148 F.Scaloni, L.Federici, M.Brunori, and S.Gianni (2010).
Deciphering the folding transition state structure and denatured state properties of nucleophosmin C-terminal domain.
  Proc Natl Acad Sci U S A, 107, 5447-5452.  
20673208 N.M.Vladimirova, N.V.Lobanova, and N.A.Potapenko (2010).
State of oncomarker protein B23/nucleophosmin in HeLa cells.
  Biochemistry (Mosc), 75, 851-860.  
20202892 R.A.Bauer, J.M.Wurst, and D.S.Tan (2010).
Expanding the range of 'druggable' targets with natural product-based libraries: an academic perspective.
  Curr Opin Chem Biol, 14, 308-314.  
19516275 B.Falini, N.Bolli, A.Liso, M.P.Martelli, R.Mannucci, S.Pileri, and I.Nicoletti (2009).
Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: molecular basis and clinical implications.
  Leukemia, 23, 1731-1743.  
19770764 B.Falini, P.Sportoletti, and M.P.Martelli (2009).
Acute myeloid leukemia with mutated NPM1: diagnosis, prognosis and therapeutic perspectives.
  Curr Opin Oncol, 21, 573-581.  
19005479 N.Bolli, M.F.De Marco, M.P.Martelli, B.Bigerna, A.Pucciarini, R.Rossi, R.Mannucci, N.Manes, V.Pettirossi, S.A.Pileri, I.Nicoletti, and B.Falini (2009).
A dose-dependent tug of war involving the NPM1 leukaemic mutant, nucleophosmin, and ARF.
  Leukemia, 23, 501-509.  
19761432 N.Meani, and M.Alcalay (2009).
Role of nucleophosmin in acute myeloid leukemia.
  Expert Rev Anticancer Ther, 9, 1283-1294.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.