ArticleProceedings of the National Academy of Sciences of the United States of America2007
Structure-based discovery of an inhibitor of Arf activation by Sec7 domains through targeting of protein-protein complexes.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 96 citations in OpenAlex.
- Sequence Determinants of Allosteric Back-to-front Control of the Arf Nucleotide Switch.Journal of molecular biology · 2025Article
- Golgiphagy: a novel selective autophagy to the fore.Cell & bioscience · 2024Review
- A molten globule ensemble primes Arf1-GDP for the nucleotide switch.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- The development of resistance to an inhibitor of a cellular protein reveals a critical interaction between the enterovirus protein 2C and a small GTPase Arf1.PLoS pathogens · 2023Article
- Targeting small GTPases: emerging grasps on previously untamable targets, pioneered by KRAS.Signal transduction and targeted therapy · 2023Review
- Protein-protein interfaces in molecular glue-induced ternary complexes: classification, characterization, and prediction.RSC chemical biology · 2023Review
- Role of theFrontiers in cell and developmental biology · 2022Review
- Sec71 separates Golgi stacks inJournal of cell science · 2020Article
- Natural products as modulators of eukaryotic protein secretion.Natural product reports · 2020Review
- Targeting the Small GTPase Superfamily through Their Regulatory Proteins.Angewandte Chemie (International ed. in English) · 2020Review
- Detection of the in vitro modulation of Plasmodium falciparum Arf1 by Sec7 and ArfGAP domains using a colorimetric plate-based assay.Scientific reports · 2020Article
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- PH-domain-binding inhibitors of nucleotide exchange factor BRAG2 disrupt Arf GTPase signaling.Nature chemical biology · 2019Article
- Small-molecule screening yields a compound that inhibits the cancer-associated transcription factor Hes1 via the PHB2 chaperone.The Journal of biological chemistry · 2018Article
- Article
- Combined targeting of Arf1 and Ras potentiates anticancer activity for prostate cancer therapeutics.Journal of experimental & clinical cancer research : CR · 2017Article
- Article
- Suppression of breast cancer metastasis through the inactivation of ADP-ribosylation factor 1.Oncotarget · 2016Article
- ARHGEF15 overexpression worsens the prognosis in patients with pancreatic ductal adenocarcinoma through enhancing the motility and proliferative activity of the cancer cells.Molecular cancer · 2016Article
- Prospects on strategies for therapeutically targeting oncogenic regulatory factors by small-molecule agents.Journal of cellular biochemistry · 2014Review
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Small molecules that produce nonfunctional protein-protein complexes are an alternative to competitive inhibitors for the inhibition of protein functions. Here we target the activation of the small GTP-binding protein Arf1, a major regulator of membrane traffic, by the Sec7 catalytic domain of its guanine nucleotide exchange factor ARNO. The crystal structure of the Arf1-GDP/ARNO complex, which initiates the exchange reaction, was used to discover an inhibitor, LM11, using in silico screening of a flexible pocket near the Arf1/ARNO interface. Using fluorescence kinetics and anisotropy, NMR spectroscopy and mutagenesis, we show that LM11 acts following a noncompetitive mechanism in which the inhibitor targets both Arf1-GDP and the Arf1-GDP/ARNO complex and produces a nonfunctional Arf-GDP/ARNO complex whose affinity is similar to that of the native complex. In addition, LM11 recognizes features of both Arf and ARNO near the Arf/Sec7 interface, a characteristic reminiscent of the paradigm interfacial inhibitor Brefeldin A. We then show that LM11 is a cell-active inhibitor that impairs Arf-dependent trafficking structures at the Golgi. Furthermore, LM11 inhibits ARNO-dependent migration of Madin-Darby canine kidney (MDCK) cells, demonstrating that ARNO is a target of LM11 in cells. Remarkably, LM11 inhibits the activation of Arf1 but not Arf6 in vitro, pointing to a possible synergy between Arf1 and Arf6 activation by ARNO in cell migration. Our design method shows that flexible regions in protein-protein complexes provide drugable sites with the potential to develop novel tools for investigating and inhibiting signaling pathways.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.