Cardiac decompensation and promiscuous prenylation of small GTPases in cardiomyocytes in response to local mevalonate pathway disruption†

Rapid development of bacterial resistance has led to an urgent need to find new druggable targets for antibiotics. In this context, residue-specific chemoproteomic approaches enable proteome-wide identification of binding sites for covalent inhibitors. Here, we describe isotopically labeled desthiobiotin azide (isoDTB) tags that are easily synthesized, shorten the chemoproteomic workflow and allow an increased coverage of cysteines in bacterial systems. We quantify 59% of all cysteines in essential proteins in <i>Staphylococcus aureus</i> and discover 88 cysteines with high reactivity, which correlates with functional importance. Furthermore, we identify 268 cysteines that are engaged by covalent ligands. We verify inhibition of HMG-CoA synthase, which will allow addressing the bacterial mevalonate pathway through a new target. Overall, a comprehensive map of the bacterial cysteinome is obtained, which will facilitate the development of antibiotics with novel modes-of-action.

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Faculty Opinions recommendation of Switch-of-function mutants based on morphology classification of Ras superfamily small GTPases.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1013446.191360 ◽

2003 ◽

Author(s):

Philippe I Bastiaens

Keyword(s):

Small Gtpases ◽

Ras Superfamily

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Faculty Opinions recommendation of Coxsackievirus entry across epithelial tight junctions requires occludin and the small GTPases Rab34 and Rab5.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1099499.555773 ◽

2008 ◽

Author(s):

Judith White

Keyword(s):

Tight Junctions ◽

Small Gtpases ◽

Epithelial Tight Junctions

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Faculty Opinions recommendation of Regulation of podocalyxin trafficking by Rab small GTPases in 2D and 3D epithelial cell cultures.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726324594.793520456 ◽

2016 ◽

Author(s):

Martin Lowe

Keyword(s):

Epithelial Cell ◽

Cell Cultures ◽

Small Gtpases ◽

Epithelial Cell Cultures ◽

2D And 3D

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Faculty Opinions recommendation of The mevalonate pathway is a druggable target for vaccine adjuvant discovery.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.734088275.793553976 ◽

2018 ◽

Author(s):

Philippe Saas ◽

Etienne Daguindau

Keyword(s):

Mevalonate Pathway ◽

Vaccine Adjuvant

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Exploring Proteomic Drug Targets, Therapeutic Strategies and Protein - Protein Interactions in Cancer: Mechanistic View

Current Cancer Drug Targets ◽

10.2174/1568009618666180803104631 ◽

2019 ◽

Vol 19 (6) ◽

pp. 430-448 ◽

Cited By ~ 1

Author(s):

Khalid Bashir Dar ◽

Aashiq Hussain Bhat ◽

Shajrul Amin ◽

Syed Anjum ◽

Bilal Ahmad Reshi ◽

...

Keyword(s):

Protein Interactions ◽

High Throughput Screening ◽

Critical Role ◽

Cancer Therapeutics ◽

Adaptor Proteins ◽

Therapeutic Strategies ◽

Small Gtpases ◽

Beta Catenin ◽

Protein Protein Interactions ◽

Apoptosis Protein

Protein-Protein Interactions (PPIs) drive major signalling cascades and play critical role in cell proliferation, apoptosis, angiogenesis and trafficking. Deregulated PPIs are implicated in multiple malignancies and represent the critical targets for treating cancer. Herein, we discuss the key protein-protein interacting domains implicated in cancer notably PDZ, SH2, SH3, LIM, PTB, SAM and PH. These domains are present in numerous enzymes/kinases, growth factors, transcription factors, adaptor proteins, receptors and scaffolding proteins and thus represent essential sites for targeting cancer. This review explores the candidature of various proteins involved in cellular trafficking (small GTPases, molecular motors, matrix-degrading enzymes, integrin), transcription (p53, cMyc), signalling (membrane receptor proteins), angiogenesis (VEGFs) and apoptosis (BCL-2family), which could possibly serve as targets for developing effective anti-cancer regimen. Interactions between Ras/Raf; X-linked inhibitor of apoptosis protein (XIAP)/second mitochondria-derived activator of caspases (Smac/DIABLO); Frizzled (FRZ)/Dishevelled (DVL) protein; beta-catenin/T Cell Factor (TCF) have also been studied as prospective anticancer targets. Efficacy of diverse molecules/ drugs targeting such PPIs although evaluated in various animal models/cell lines, there is an essential need for human-based clinical trials. Therapeutic strategies like the use of biologicals, high throughput screening (HTS) and fragment-based technology could play an imperative role in designing cancer therapeutics. Moreover, bioinformatic/computational strategies based on genome sequence, protein sequence/structure and domain data could serve as competent tools for predicting PPIs. Exploring hot spots in proteomic networks represents another approach for developing targetspecific therapeutics. Overall, this review lays emphasis on a productive amalgamation of proteomics, genomics, biochemistry, and molecular dynamics for successful treatment of cancer.

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