A. Manglik

Molecular basis of proton-sensing by G protein-coupled receptors

The paper identifies proton-sensing mechanisms in GPCRs using cryo-EM and deep mutational scanning, revealing a network of residues rather than a single site for proton recognition.

GPR161 structure uncovers the redundant role of sterol-regulated ciliary cAMP signaling in the Hedgehog pathway

The paper determines the cryo-EM structure of active GPR161 bound to Gs, revealing sterol binding and its role in ciliary cAMP signaling, while showing that sterol binding is not essential for Hedgehog pathway suppression.

Anionic phospholipids determine G protein coupling selectivity at distinct subcellular membrane compartments

This study shows that anionic phospholipids like PI(4,5)P2 enable promiscuous GPCR coupling to both cognate and non-cognate G proteins at the plasma membrane, while restricting coupling to cognate G proteins in other compartments.

Structural basis of odorant recognition by a human odorant receptor

The paper determines the structure of a human odorant receptor bound to propionate, revealing how odorant recognition and activation occur through specific molecular interactions.

Discrete GPCR-triggered endocytic modes enable β-arrestins to flexibly regulate cell signaling

This study identifies two distinct GPCR-triggered endocytic modes in β-arrestins, each with different signaling outcomes and receptor-specific activation.

Structure-based Discovery of Conformationally Selective Inhibitors of the Serotonin Transporter

The paper identifies two novel inhibitors of the serotonin transporter that selectively target the inward-open conformation, showing improved potency and reduced off-target effects compared to existing drugs.

Autoantibody and hormone activation of the thyrotropin G protein-coupled receptor

This study determines cryogenic-electron microscopy structures of active and inactive TSHR, revealing how autoantibodies and TSH activate the receptor through similar conformational changes.

Fusion protein strategies for cryo-EM study of G protein-coupled receptors

The paper explores fusion protein strategies to improve cryo-EM structure determination of GPCRs without signaling proteins, achieving resolutions of 3.4 and 3.7 Å for two receptors.

Selective G protein signaling driven by Substance P-Neurokinin Receptor structural dynamics

This study investigates how different agonists of the NK1R receptor influence G-protein signaling through structural dynamics and extracellular loop interactions.

Bivalent binding of a fully human IgG to the SARS-CoV-2 spike proteins reveals mechanisms of potent neutralization

This study identifies a potent SARS-CoV-2 neutralizing antibody, 5A6, that binds bivalently to two RBDs on the spike protein, showing resistance to key mutations.

Smoothened Transduces Hedgehog Signals via Activity-Dependent Sequestration of PKA Catalytic Subunits

This study reveals that Smoothened (SMO) activates GLI transcription factors by sequestering PKA catalytic subunits at the membrane, bypassing traditional GPCR signaling mechanisms.

Structure of human ferroportin bound to hepcidin reveals mechanisms of iron homeostasis

This study determines the cryo-EM structures of human ferroportin bound to hepcidin and identifies mechanisms of iron homeostasis regulation.

Agonist-selective recruitment of engineered protein probes and of GRK2 by opioid receptors in living cells

The paper develops a cell-based assay to study agonist-selective recruitment of engineered protein probes and GRK2 by opioid receptors in living cells, showing differential recruitment by distinct opioid ligands.

Hedgehog pathway activation through conformational blockade of the Patched sterol conduit

This paper develops a nanobody agonist that activates the Hedgehog pathway by stabilizing an alternative conformation of Patched1, disrupting its sterol conduit and providing a new approach for transporter-related drug development.

Platform for rapid nanobody discovery in vitro

This paper presents an in vitro platform for rapid nanobody discovery using yeast surface display, demonstrating its application to various antigens including lipid flippase and G protein-coupled receptors.