Aurélien Laurent Jean-Charles Oggier

Computational design of dynamic receptor—peptide signaling complexes applied to chemotaxis

Patrick Daniel Barth, Andreas Füglistaler, Mahdi Hijazi, Robert Everett Jefferson, Aurélien Laurent Jean-Charles Oggier, Ana Paola Rico Villarreal

Engineering protein biosensors that sensitively respond to specific biomolecules by triggering precise cellular responses is a major goal of diagnostics and synthetic cell biology. Previous biosensor designs have largely relied on binding structurally well-defined molecules. In contrast, approaches that couple the sensing of flexible compounds to intended cellular responses would greatly expand potential biosensor applications. Here, to address these challenges, we develop a computational strategy for designing signaling complexes between conformationally dynamic proteins and peptides. To demonstrate the power of the approach, we create ultrasensitive chemotactic receptor—peptide pairs capable of eliciting potent signaling responses and strong chemotaxis in primary human T cells. Unlike traditional approaches that engineer static binding complexes, our dynamic structure design strategy optimizes contacts with multiple binding and allosteric sites accessible through dynamic conformational ensembles to achieve strongly enhanced signaling efficacy and potency. Our study suggests that a conformationally adaptable binding interface coupled to a robust allosteric transmission region is a key evolutionary determinant of peptidergic GPCR signaling systems. The approach lays a foundation for designing peptide-sensing receptors and signaling peptide ligands for basic and therapeutic applications.

2023

Computational design of ultrasensitive flexible peptide:receptor signaling complexes for enhanced chemotaxis

Patrick Daniel Barth, Andreas Füglistaler, Mahdi Hijazi, Robert Everett Jefferson, Aurélien Laurent Jean-Charles Oggier, Ana Paola Rico Villarreal

Engineering biosensors that sensitively recognize specific biomolecules and trigger functional cellular responses is a holy grail of diagnostics and synthetic cell biology. Biosensor design approaches have mostly focused on binding structurally well-defined molecules. Coupling the sensing of flexible compounds to complex cellular responses would considerably expand biosensor applications, but remains challenging. We developed a computational strategy for designing highly sensitive receptor biosensors of flexible peptides. Using the method, we created ultrasensitive chemotactic GPCR:peptide pairs capable of eliciting potent chemotaxis in human primary T cells. Through mutual induced fit, our flexible structure design approach enhanced peptide contacts with binding and allosteric sites in the ligand pocket to achieve unprecedented signaling efficacy and potency. The approach paves the road for designing peptide-sensing receptors and expanding the biosensor toolbox for basic and therapeutic applications.

bioRxiv2022

Computational rewiring of allosteric pathways reprograms GPCR selective responses to ligands

Patrick Daniel Barth, Mahdi Hijazi, Dániel Kéri, Aurélien Laurent Jean-Charles Oggier

G-protein-coupled receptors (GPCRs) are the largest class of cell surface receptors and drug targets, and respond to a wide variety of chemical stimuli to activate diverse cellular functions. Understanding and predicting how ligand binding triggers a specific signaling response is critical for drug discovery and design but remains a major challenge. Here, computational design of GPCR allosteric functions is used to uncover the mechanistic relationships between agonist ligand chemistry, receptor sequence, structure, dynamics and allosteric signaling in the dopamine D2 receptor. Designed gain of function D2 variants for dopamine displayed very divergent G-protein signaling responses to other ligand agonists that strongly correlated with ligand structural similarity. Consistent with these observations, computational analysis revealed distinct topologies of allosteric signal transduction pathways for each ligand-bound D2 pair that were perturbed differently by the designs. We leveraged these findings by rewiring ligand-specific pathways and designed receptors with highly selective ligand responses. Overall, our study suggests that distinct ligand agonists can activate a given signaling effector through specific “allosteric activator” moieties that engage partially independent signal transmission networks in GPCRs. The results provide a mechanistic framework for understanding and predicting the impact of sequence polymorphism on receptor pharmacology, informing selective drug design and rationally designing receptors with highly selective ligand responses for basic and therapeutic applications.

bioRxiv2022

The NAD-Booster Nicotinamide Riboside Potently Stimulates Hematopoiesis through Increased Mitochondrial Clearance

Johan Auwerx, Carlos Canto Alvarez, George Coukos, Bart Deplancke, Martin Ehrbar, Sonja Giger, Mukul Girotra, Vasco Ledebur de Antas de Campos, Matthias Lütolf, Olaia Maria Naveiras Torres-Quiroga, Gennady Nikitin, Aurélien Laurent Jean-Charles Oggier, Eija Riitta Pirinen, Simone Ragusa, Pernille Yde Rainer, Joanna Ratajczak, Shanti Rojas-Sutterlin, Pedro Romero, Dongryeol Ryu, Federico Sizzano, Loïc Tauzin, Vincent Trachsel, Josefine Catharina Pedersen Tratwal, Nicola Vannini, Yannick Lionel Yersin

It has been recently shown that increased oxidative phosphorylation, as reflected by increased mitochondrial activity, together with impairment of the mitochondrial stress response, can severely compromise hematopoietic stem cell (HSC) regeneration. Here we show that the NAD(+)-boosting agent nicotinamide riboside (NR) reduces mitochondrial activity within HSCs through increased mitochondrial clearance, leading to increased asymmetric HSC divisions. NR dietary supplementation results in a significantly enlarged pool of progenitors, without concurrent HSC exhaustion, improves survival by 80%, and accelerates blood recovery after murine lethal irradiation and limiting-HSC transplantation. In immune-deficient mice, NR increased the production of human leucocytes from hCD34+ progenitors. Our work demonstrates for the first time a positive effect of NAD(+)-boosting strategies on the most primitive blood stem cells, establishing a link between HSC mitochondrial stress, mitophagy, and stem-cell fate decision, and unveiling the potential of NR to improve recovery of patients suffering from hematological failure including post chemo- and radiotherapy.

CELL PRESS2019

Aurélien Laurent Jean-Charles Oggier

Computational design of dynamic receptor—peptide signaling complexes applied to chemotaxis

Computational design of ultrasensitive flexible peptide:receptor signaling complexes for enhanced chemotaxis

Computational rewiring of allosteric pathways reprograms GPCR selective responses to ligands

The NAD-Booster Nicotinamide Riboside Potently Stimulates Hematopoiesis through Increased Mitochondrial Clearance

The NAD plus Salvage Pathway Potently Stimulates Hematopoiesis through Increased Mitochondrial Clearance and Asymmetric Division

Computational design of dynamic receptor—peptide signaling complexes applied to chemotaxis

Computational design of ultrasensitive flexible peptide:receptor signaling complexes for enhanced chemotaxis

Computational rewiring of allosteric pathways reprograms GPCR selective responses to ligands

The NAD-Booster Nicotinamide Riboside Potently Stimulates Hematopoiesis through Increased Mitochondrial Clearance

The NAD plus Salvage Pathway Potently Stimulates Hematopoiesis through Increased Mitochondrial Clearance and Asymmetric Division