Allosteric Binding-Mediated Suppression on Activity of G12D KRAS Recognized via Markov State Model and Communication Pathway

The KRAS G12D mutation is one of the most common oncogenic lesions in human tumors, especially in pancreatic ductal adenocarcinoma. The monobodies 12D1 and 12D5 exhibit high selectivity for the G12D mutant of KRAS compared to the wild-type (WT) form. However, the structural and dynamic factors underlying this specificity are still not fully understood. To explore this, we analyzed the transition direction of conformations, allosteric communication pathways, and residue-residue interaction networks at the protein-protein interface. The G12D mutation causes the switch regions to transition from a closed state to an open state. Binding of 12D1 and 12D5 restores this abnormal transition. Additionally, the G12D…

• NS
  Natural Science Foundation of Shandong Province

  Award: ZR2021MA069
• SJ
  Shandong Jiaotong University

  Award: TJXZ202204