GTP-binding protein regulators

GTP-binding protein regulators are proteins that regulate the function of small G proteins (heterotrimeric guanine nucelotide-binding peripheral membrane proteins involved in signal transduction). These include GTPase-activating proteins (GAPs) that accelerate GTP hydrolysis, guanine nucleotide dissociation inhibitors (GDIs) that prevent GDP dissociation, and guanine nucleotide exchange factors (GEFs) that facilitate exchange of GDP for GTP.

Latest Research and Reviews

  • Reviews |

    Effective therapeutic strategies to target RAS-mutant cancers have proved elusive, but in the past few years, several promising strategies have been tested in clinical trials. The authors describe historical and ongoing therapeutic approaches based on the direct or indirect targeting of RAS.

    • Meagan B. Ryan
    •  & Ryan B. Corcoran
  • Reviews |

    Identifying ligands of G protein-coupled receptors (GPCRs) that elicit biased downstream signalling is an established strategy for separating the desired and unwanted effects of these receptors. Campbell and Smrcka describe how inhibiting the downstream G proteins themselves could also be used to bias GPCR signalling, as well as block pathways shared by multiple GPCRs involved in complex diseases, and discuss how the currently available G protein ligands could be optimized to generate therapeutic leads.

    • Adrian P. Campbell
    •  & Alan V. Smrcka
  • Research | | open

    Rab11 GTPases are involved in various cellular processes but their activation by guanine nucleotide exchange factors (GEFs) is not fully understood. Here, the authors present a structural and biochemical analysis of Rab11 bound to the GEF SH3BP5, providing insights how Rab-GEF specificity is achieved.

    • Meredith L. Jenkins
    • , Jean Piero Margaria
    • , Jordan T. B. Stariha
    • , Reece M. Hoffmann
    • , Jacob A. McPhail
    • , David J. Hamelin
    • , Martin J. Boulanger
    • , Emilio Hirsch
    •  & John E. Burke
  • Research |

    Kinetic and structural analyses show that the activity of two covalent inhibitors of human KRASG12C, which initially bind to a shallow pocket with low affinity, is driven by KRAS-mediated catalysis of the chemical reaction with Cys12.

    • Rasmus Hansen
    • , Ulf Peters
    • , Anjali Babbar
    • , Yuching Chen
    • , Jun Feng
    • , Matthew R. Janes
    • , Lian-Sheng Li
    • , Pingda Ren
    • , Yi Liu
    •  & Patrick P. Zarrinkar
  • Research | | open

    The bacterial protease GtgE is involved in the establishment of Salmonellosis. Here the authors provide a structural and biochemical analysis of GtgE that sheds light on the molecular mechanisms of reprogramming infected host cells via site-specific proteolytic cleavage of the vesicular trafficking regulator Rab32.

    • Rudolf Wachtel
    • , Bastian Bräuning
    • , Sophie L. Mader
    • , Felix Ecker
    • , Ville R. I. Kaila
    • , Michael Groll
    •  & Aymelt Itzen

News and Comment

  • News and Views |

    Traditional approaches to covalent drug design postulate that noncovalent binding affinity (Ki) should be in the nanomolar range for the lead compound to be attractive. A study by Hansen et al. suggests that covalent K-Ras inhibitors can have weak noncovalent binding affinity yet have fast chemical reactivity (kinact), because K-Ras enhances the covalent reactivity of bound inhibitor, similarly to how enzymes activate their substrates.

    • Alexander V. Statsyuk
  • News and Views |

    Drosophila Skywalker regulates the GTPase Rab35, thereby controlling the turnover of synaptic-vesicle proteins. A new crystal structure of the TBC domain of Skywalker reveals an unexpected phosphoinositide-binding pocket, which is critical for synaptic function and is disrupted in DOORS syndrome–causing mutations in the human Skywalker homolog TBC1D24.

    • Steven J Del Signore
    •  & Avital A Rodal