1 Ocak 2023 Dergi makalesi Açık Erişim

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

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  <dc:creator>Altiner, Pinar</dc:creator>
  <dc:creator>Cinaroglu, Suleyman Selim</dc:creator>
  <dc:creator>Timucin, Ahmet Can</dc:creator>
  <dc:creator>Timucin, Emel</dc:creator>
  <dc:date>2023-01-01</dc:date>
  <dc:description>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.</dc:description>
  <dc:identifier>https://aperta.ulakbim.gov.trrecord/271298</dc:identifier>
  <dc:identifier>oai:aperta.ulakbim.gov.tr:271298</dc:identifier>
  <dc:rights>info:eu-repo/semantics/openAccess</dc:rights>
  <dc:rights>http://www.opendefinition.org/licenses/cc-by</dc:rights>
  <dc:source>SCIENTIFIC REPORTS 13(1) 15</dc:source>
  <dc:title>Computational completion of the Aurora interaction region of N-Myc in the Aurora a kinase complex</dc:title>
  <dc:type>info:eu-repo/semantics/article</dc:type>
  <dc:type>publication-article</dc:type>
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