The Gpn1, Gpn2, and Gpn3 proteins are members of the GTPase GPN family; yeast Npa3 is an orthologue of the human Gpn1 protein. These proteins play a crucial role in the nuclear accumulation of RNA polymerase II, functioning as molecular chaperones. The crystallographic structures of Npa3 reveal open and closed conformations, which are dependent on the bound guanine nucleotide (GMPPCP or GDP, respectively). The open conformation of Npa3 exhibits a hydrophobic pocket proposed to be essential for the recognition and binding of specific peptides of RNA polymerase II, contributing to its biogenesis; however, structural data on these complexes remain unavailable. In this work, we present in silico models of the interactions between the crystallographic structure of monomeric Npa3 in its open conformation and yeast RNA polymerase II peptides, generated through flexible computational docking. To identify inhibitors of these interactions, potentially useful in understanding the molecular and cellular functions of these proteins, we performed molecular docking experiments using a designed library of FDA-approved compounds on both the Npa3 structure and a homology model of human Gpn1. Our analysis identified potential inhibitors, including atovaquone for both Npa3 and Gpn1 (docking scores: -14.4 and -13.5 kcal/mol, respectively) and tibolone for Npa3 (-13.6 kcal/mol), following flexible docking optimization. Additionally, our docking models suggest key residues in Npa3 such as F143 and W179, which may be critical for recognizing RNA polymerase II subunits and drug-like molecules. These findings can be further explored through biochemical and mutagenesis studies to assess their roles in RNA polymerase II recognition.

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Journal Article

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Muñiz-Luna JA, Santiago Á, Cristóbal-Mondragón GR, Calera MR, Sánchez-Olea R, Pastor N

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