1 Ocak 2023 Dergi makalesi Açık Erişim

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

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{
  "@context": "https://schema.org/", 
  "@id": 271298, 
  "@type": "ScholarlyArticle", 
  "creator": [
    {
      "@type": "Person", 
      "affiliation": "Univ Toulouse III Paul Sabatier UT3, CNRS, Inst Pharmacol & Biol Struct IPBS, F-31077 Toulouse, France", 
      "name": "Altiner, Pinar"
    }, 
    {
      "@type": "Person", 
      "affiliation": "Univ Oxford, Dept Biochem, South Parks Rd, Oxford OX1 3QU, England", 
      "name": "Cinaroglu, Suleyman Selim"
    }, 
    {
      "@type": "Person", 
      "affiliation": "Acibadem Univ, Fac Engn & Nat Sci, Dept Mol Biol & Genet, TR-34752 Istanbul, Turkiye", 
      "name": "Timucin, Ahmet Can"
    }, 
    {
      "@type": "Person", 
      "affiliation": "Acibadem Univ, Sch Med, Dept Biostat & Med Informat, TR-34752 Istanbul, Turkiye", 
      "name": "Timucin, Emel"
    }
  ], 
  "datePublished": "2023-01-01", 
  "description": "<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>", 
  "headline": "Computational completion of the Aurora interaction region of N-Myc in the Aurora a kinase complex", 
  "identifier": 271298, 
  "image": "https://aperta.ulakbim.gov.tr/static/img/logo/aperta_logo_with_icon.svg", 
  "license": "http://www.opendefinition.org/licenses/cc-by", 
  "name": "Computational completion of the Aurora interaction region of N-Myc in the Aurora a kinase complex", 
  "url": "https://aperta.ulakbim.gov.tr/record/271298"
}