Synthesis and Effect of Conformationally Locked Carbocyclic Guanine Nucleotides on Dynamin

Kiran S. Toti, John R. Jimah, Veronica Salmaso, Jenny E. Hinshaw, Kenneth A. Jacobson

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Guanine nucleotides can flip between a North and South conformation in the ribose moiety. To test the enzymatic activity of GTPases bound to nucleotides in the two conformations, we generated methanocarba guanine nucleotides in the North or South envelope conformations, i.e., (N)-GTP and (S)-GTP, respectively. With dynamin as a model system, we examined the effects of (N)-GTP and (S)-GTP on dynamin-mediated membrane constriction, an activity essential for endocytosis. Dynamin membrane constriction and fission activity are dependent on GTP binding and hydrolysis, but the effect of the conformational state of the GTP nucleotide on dynamin activity is not known. After reconstituting dynamin-mediated lipid tubulation and membrane constriction in vitro, we observed via cryo-electron microscopy (cryo-EM) that (N)-GTP, but not (S)-GTP, enables the constriction of dynamin-decorated lipid tubules. These findings suggest that the activity of dynamin is dependent on the conformational state of the GTP nucleotide. However, a survey of nucleotide ribose conformations associated with dynamin structures in nature shows almost exclusively the (S)-conformation. The explanation for this mismatch of (N) vs. (S) required for GTP analogues in a dynamin-mediated process will be addressed in future studies.

Original languageEnglish (US)
Article number584
Issue number4
StatePublished - Apr 2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Biochemistry


  • GTPase
  • conformationally locked
  • dynamin
  • guanine nucleotide
  • membrane fission
  • methanocarba


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