1 Ocak 2023 Dergi makalesi Açık Erişim

Altiner, Pinar; Cinaroglu, Suleyman Selim; Timucin, Ahmet Can; Timucin, Emel

Citation Style Language JSON

{
  "DOI": "10.1038/s41598-023-45272-3", 
  "abstract": "<p>Inhibiting protein-protein interactions of the Myc family is a viable pharmacological strategy for modulation of the levels of Myc oncoproteins in cancer. Aurora A kinase (AurA) and N-Myc interaction is one of the most attractive targets of this strategy because formation of this complex blocks proteasomal degradation of N-Myc in neuroblastoma. Two crystallization studies have captured this complex (PDB IDs: 5g1x, 7ztl), partially resolving the AurA interaction region (AIR) of N-Myc. Prompted by the missing N-Myc fragment in these crystal structures, we modeled the complete structure between AurA and N-Myc, and comprehensively analyzed how the incomplete and complete N-Myc behave in complex by molecular dynamics simulations. Molecular dynamics simulations of the incomplete PDB complex (5g1x) repeatedly showed partial dissociation of the short N-Myc fragment (61-89) from the kinase. The missing N-Myc (19-60) fragment was modeled utilizing the N-terminal lobe of AurA as the protein-protein interaction surface, wherein TPX2, a well-known partner of AurA, also binds. Binding free energy calculations along with flexibility analysis confirmed that the complete AIR of N-Myc stabilizes the complex, accentuating the N-terminal lobe of AurA as a binding site for the missing N-Myc fragment (19-60). We further generated additional models consisting of only the missing N-Myc (19-60), and the fused form of TPX2 (7-43) and N-Myc (61-89). These partners also formed more stable interactions with the N-terminal lobe of AurA than did the incomplete N-Myc fragment (61-89) in the 5g1x complex. Altogether, this study provides structural insights into the involvement of the N-terminus of the AIR of N-Myc and the N-terminal lobe of AurA in formation of a stable complex, reflecting its potential for effective targeting of N-Myc.</p>", 
  "author": [
    {
      "family": "Altiner", 
      "given": " Pinar"
    }, 
    {
      "family": "Cinaroglu", 
      "given": " Suleyman Selim"
    }, 
    {
      "family": "Timucin", 
      "given": " Ahmet Can"
    }, 
    {
      "family": "Timucin", 
      "given": " Emel"
    }
  ], 
  "container_title": "SCIENTIFIC REPORTS", 
  "id": "271298", 
  "issue": "1", 
  "issued": {
    "date-parts": [
      [
        2023, 
        1, 
        1
      ]
    ]
  }, 
  "page": "15", 
  "title": "Computational completion of the Aurora interaction region of N-Myc in the Aurora a kinase complex", 
  "type": "article-journal", 
  "volume": "13"
}