1 Ocak 2023 Dergi makalesi Açık Erişim

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

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  <identifier identifierType="URL">https://aperta.ulakbim.gov.tr/record/271298</identifier>
  <creators>
    <creator>
      <creatorName>Altiner, Pinar</creatorName>
      <givenName>Pinar</givenName>
      <familyName>Altiner</familyName>
      <affiliation>Univ Toulouse III Paul Sabatier UT3, CNRS, Inst Pharmacol &amp; Biol Struct IPBS, F-31077 Toulouse, France</affiliation>
    </creator>
    <creator>
      <creatorName>Cinaroglu, Suleyman Selim</creatorName>
      <givenName>Suleyman Selim</givenName>
      <familyName>Cinaroglu</familyName>
      <affiliation>Univ Oxford, Dept Biochem, South Parks Rd, Oxford OX1 3QU, England</affiliation>
    </creator>
    <creator>
      <creatorName>Timucin, Ahmet Can</creatorName>
      <givenName>Ahmet Can</givenName>
      <familyName>Timucin</familyName>
      <affiliation>Acibadem Univ, Fac Engn &amp; Nat Sci, Dept Mol Biol &amp; Genet, TR-34752 Istanbul, Turkiye</affiliation>
    </creator>
    <creator>
      <creatorName>Timucin, Emel</creatorName>
      <givenName>Emel</givenName>
      <familyName>Timucin</familyName>
      <affiliation>Acibadem Univ, Sch Med, Dept Biostat &amp; Med Informat, TR-34752 Istanbul, Turkiye</affiliation>
    </creator>
  </creators>
  <titles>
    <title>Computational Completion Of The Aurora Interaction Region Of N-Myc In The Aurora A Kinase Complex</title>
  </titles>
  <publisher>Aperta</publisher>
  <publicationYear>2023</publicationYear>
  <dates>
    <date dateType="Issued">2023-01-01</date>
  </dates>
  <resourceType resourceTypeGeneral="Text">Journal article</resourceType>
  <alternateIdentifiers>
    <alternateIdentifier alternateIdentifierType="url">https://aperta.ulakbim.gov.tr/record/271298</alternateIdentifier>
  </alternateIdentifiers>
  <relatedIdentifiers>
    <relatedIdentifier relatedIdentifierType="DOI" relationType="IsIdenticalTo">10.1038/s41598-023-45272-3</relatedIdentifier>
  </relatedIdentifiers>
  <rightsList>
    <rights rightsURI="http://www.opendefinition.org/licenses/cc-by">Creative Commons Attribution</rights>
    <rights rightsURI="info:eu-repo/semantics/openAccess">Open Access</rights>
  </rightsList>
  <descriptions>
    <description descriptionType="Abstract">&lt;p&gt;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.&lt;/p&gt;</description>
  </descriptions>
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