Pharmacology | Nature

Article | 10 April 2024

Bitter taste receptor activation by cholesterol and an intracellular tastant

Cryo-electron microscopy structures of the type 2 taste receptor TAS2R14 in complex with Ggust and Gi1 identify cholesterol as an orthosteric agonist and the bitter tastant cmpd28.1 as a positive allosteric modulator and agonist.

Yoojoong Kim
, Ryan H. Gumpper
& Bryan L. Roth

Article | 08 April 2024

Tumor-selective activity of RAS-GTP inhibition in pancreatic cancer

Urszula N. Wasko
, Jingjing Jiang
& Kenneth P. Olive

Article | 07 November 2023

Recognition of methamphetamine and other amines by trace amine receptor TAAR1

We report on the structures of the TAAR1–G-protein complex when bound to methamphetamine and other amines.

Heng Liu
, You Zheng
& Fei Xu

Article | 31 July 2023

Conserved class B GPCR activation by a biased intracellular agonist

A study reports an orally available small-molecule agonist that binds between a G protein and its receptor, and characterizes this new binding mode.

Li-Hua Zhao
, Qian He
& H. Eric Xu

Article
07 June 2023 | Open Access

Class B1 GPCR activation by an intracellular agonist

A new intracellular agonist-binding pocket is identified that is common to many G protein-coupled receptors, which will have implications for the development of biased compounds that target this large group of receptors.

Kazuhiro Kobayashi
, Kouki Kawakami
& Osamu Nureki

Article
03 May 2023 | Open Access

Ligand and G-protein selectivity in the κ-opioid receptor

Active-state structures of the κ-opioid receptor in complexes with the G-protein heterotrimers G_i1, G_oA, G_z and G_g provide insights into the actions of hallucinogenic opioids and G-protein-coupling specificity at the κ-opioid receptor.

Jianming Han
, Jingying Zhang
& Tao Che

Article | 15 March 2023

Structural basis of odorant recognition by a human odorant receptor

Through the use of cryo-electron microscopy and molecular dynamics stimulations, mechanistic insight into the binding of an odorant to the human odorant receptor OR51E2 is provided.

Christian B. Billesbølle
, Claire A. de March
& Aashish Manglik

Article | 08 March 2023

Molecular sensing of mechano- and ligand-dependent adhesion GPCR dissociation

A technique to detect the release of N-terminal fragments of Drosophila adhesion G-protein-coupled receptors (aGPCRs) provides insight into the dissociation of aGPCRs, and shows that receptor autoproteolysis enables non-cell-autonomous activity of aGPCRs in the brain.

Nicole Scholz
, Anne-Kristin Dahse
& Tobias Langenhan

Article | 30 November 2022

Structure-based design of bitopic ligands for the µ-opioid receptor

Bitopic functionalized ligands based on fentanyl can target the sodium ion-binding site of the mu-opioid receptor and selectively modulate downstream signalling pathways, potentially leading to safer analgesics.

Abdelfattah Faouzi
, Haoqing Wang
& Susruta Majumdar

Article
14 September 2022 | Open Access

Brain-restricted mTOR inhibition with binary pharmacology

The combination of the brain-permeable mTOR inhibitor RapaLink-1 and the brain-impermeable FKBP12 ligand RapaBlock enable brain-specific inhibition of mTOR.

Ziyang Zhang
, Qiwen Fan
& Kevan M. Shokat

Article | 08 August 2022

Autoantibody mimicry of hormone action at the thyrotropin receptor

Cryo-electron microscopy structures of the thyrotropin receptor reveal the basis for the activation of the receptor by autoantibodies in patients with Graves’ disease.

Bryan Faust
, Christian B. Billesbølle
& Aashish Manglik

Article | 08 June 2022

Structural basis of GABA reuptake inhibition

Structural determination of GAT1 using cryo-electron microscopy provides insights into the biology and pharmacology of this GABA transporter.

Zenia Motiwala
, Nanda Gowtham Aduri
& Cornelius Gati

Article | 08 December 2021

Structures of the σ₂ receptor enable docking for bioactive ligand discovery

Crystal structures of the σ₂ receptor are determined and used to perform a docking screen of nearly 500 million molecules, identifying σ₂-selective ligands and providing insight into the role of σ₂ in neuropathic pain.

Assaf Alon
, Jiankun Lyu
& Andrew C. Kruse

Article | 08 December 2021

Structural basis of inhibition of the human SGLT2–MAP17 glucose transporter

Using cryogenic electron microscopy, the structure of the human SGLT2–MAP17 complex captured in the empagliflozin-bound state reveals the inhibitory mechanism of these anti-diabetic drugs.

Yange Niu
, Rui Liu
& Lei Chen

Article | 17 November 2021

Structure, function and pharmacology of human itch receptor complexes

Cryo-electron microscopy structures of the MRGPRX2–G_i1 trimer in complex with polycationic compound 48/80 or inflammatory peptides provide insights into the sensing of cationic allergens by MRGPRX2, potentially facilitating the design of therapies to prevent unwanted pseudoallergic reactions.

Fan Yang
, Lulu Guo
& Jin-Peng Sun

Article | 08 September 2021

Positive allosteric mechanisms of adenosine A₁ receptor-mediated analgesia

MIPS521, a positive allosteric modulator of the adenosine A₁ receptor, has analgesic properties in a rat model of neuropathic pain through a mechanism by which MIPS521 stabilizes the complex between adenosine, receptor and G protein.

Christopher J. Draper-Joyce
, Rebecca Bhola
& Arthur Christopoulos

Article | 24 March 2021

Structural insights into the lipid and ligand regulation of serotonin receptors

Cryo-electron microscopy structures of three different serotonin receptors in complex with serotonin and other agonists provide insights into the role of lipids in regulating these receptors and the structural basis of ligand recognition.

Peiyu Xu
, Sijie Huang
& H. Eric Xu

Article | 09 December 2020

A non-hallucinogenic psychedelic analogue with therapeutic potential

Psychedelic alkaloids served as lead structures for the development of tabernanthalog, a non-hallucinogenic and non-toxic analogue that reduces alcohol- and heroin-seeking behaviour and produces antidepressant-like effects in rodents.

Lindsay P. Cameron
, Robert J. Tombari
& David E. Olson

Article | 22 July 2020

Structural basis of GPBAR activation and bile acid recognition

Using cryo-electron microscopy, the authors report the structures of G-protein-coupled bile acid receptor–G_s complexes and reveal the structural basis of bile acid recognition.

Fan Yang
, Chunyou Mao
& Yan Zhang

Article | 10 February 2020

Virtual discovery of melatonin receptor ligands to modulate circadian rhythms

A computational screen of an ultra-large virtual library against the structure of the melatonin receptor found nanomolar ligands, and ultimately two selective MT₁ inverse agonists that induced phase advancement of the mouse circadian clock when given at subjective dusk.

Reed M. Stein
, Hye Jin Kang
& Margarita L. Dubocovich

Article | 16 January 2020

Structure of the neurotensin receptor 1 in complex with β-arrestin 1

A cryo-electron microscopy structure of the neurotensin receptor 1 in complex with β-arrestin 1 is reported.

Weijiao Huang
, Matthieu Masureel
& Brian K. Kobilka

Article | 08 January 2020

Activation of the GLP-1 receptor by a non-peptidic agonist

The structure of GLP-1R and its G protein in complex with the small molecule TT-OAD2 sheds light on how the TT-OAD2 agonist can activate the receptor and provides insights into the development of therapeutic agents for metabolic disorders.

Peishen Zhao
, Yi-Lynn Liang
& Denise Wootten

Article | 02 January 2019

GABA_A receptor signalling mechanisms revealed by structural pharmacology

Cryo-electron microscopy structures are reported in which the full-length human α1β3γ2L GABA_A receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA, and the benzodiazepines alprazolam and diazepam.

Simonas Masiulis
, Rooma Desai
& A. Radu Aricescu

Article | 12 September 2018

Optimized arylomycins are a new class of Gram-negative antibiotics

Chemical optimization of arylomycins results in an inhibitor of bacterial type I signal peptidase that shows activity both against multidrug-resistant clinical isolates of Gram-negative bacteria in vitro and in several in vivo infection models.

Peter A. Smith
, Michael F. T. Koehler
& Christopher E. Heise

Review Article | 04 July 2018

Structural insights into G-protein-coupled receptor allostery

High-resolution structural studies of GPCRs have led to insights into the role of allostery in GPCR-mediated signal transduction.

David M. Thal
, Alisa Glukhova
& Arthur Christopoulos

Article | 20 June 2018

Structure of the adenosine-bound human adenosine A₁ receptor–G_i complex

The cryo-electron microscopy structure of the human adenosine A₁ receptor in complex with adenosine and heterotrimeric G_i2 protein provides molecular insights into receptor and G-protein selectivity.

Christopher J. Draper-Joyce
, Maryam Khoshouei
& Arthur Christopoulos

Article | 13 June 2018

Structure of the µ-opioid receptor–G_i protein complex

A cryo-electron structure of the µ-opioid receptor in complex with the peptide agonist DAMGO and the inhibitory G protein G_i reveals structural determinants of its G protein-binding specificity.

Antoine Koehl
, Hongli Hu
& Brian K. Kobilka

Letter | 24 January 2018

Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone

An X-ray structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone reveals an extended binding pocket and indicates structural features that could be used to design drugs that specifically target the D2 receptor.

Sheng Wang
, Tao Che
& Bryan L. Roth

Letter | 16 August 2017

Vaccine-driven pharmacodynamic dissection and mitigation of fenethylline psychoactivity

A vaccine-driven approach shows that the prominent stimulant features of the psychoactive profile of fenethylline can be attributed to amphetamine, with synergistic support from theophylline, and no direct contributions from the parent drug molecule.

Cody J. Wenthur
, Bin Zhou
& Kim D. Janda

Article | 31 May 2017

Crystal structure of the GLP-1 receptor bound to a peptide agonist

The solved crystal structure of the GLP-1 receptor bound to a truncated agonist enables the design of synthetic agonists that exhibit potent activity in vivo.

Ali Jazayeri
, Mathieu Rappas
& Fiona H. Marshall

Letter | 26 April 2017

Structural insight into allosteric modulation of protease-activated receptor 2

Crystal structures of protease-activated receptor 2 (PAR2) in complex with two different antagonist ligands and with a blocking antibody reveal binding sites that are distinct from those found on PAR1, offering new leads for structure-based drug design.

Robert K. Y. Cheng
, Cédric Fiez-Vandal
& Niek Dekker

Article | 24 April 2017

Phase-plate cryo-EM structure of a class B GPCR–G-protein complex

Volta phase-plate cryo-electron microscopy reveals the structure of the full-length calcitonin receptor in complex with its peptide ligand and Gα_sβγ.

Yi-Lynn Liang
, Maryam Khoshouei
& Patrick M. Sexton

Letter | 22 March 2017

The allosteric inhibitor ABL001 enables dual targeting of BCR–ABL1

The selective allosteric ABL1 inhibitor ABL001 (asciminib) represents a new inhibitory mechanism for BCR–ABL1-driven malignancies, and its efficacy and evolving mechanisms of resistance do not overlap with those of other BCR–ABL1 kinase inhibitors.

Andrew A. Wylie
, Joseph Schoepfer
& William R. Sellers

Letter | 07 December 2016

Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists

The crystal structure of CCR2 chemokine receptor in a complex with two different antagonists—one orthosteric the other allosteric—which functionally cooperate to inhibit CCR2.

Yi Zheng
, Ling Qin
& Tracy M. Handel

Review Article | 01 December 2016

Organization and functions of mGlu and GABA_B receptor complexes

This Review discusses current knowledge of the structure, function and interactions of the metabotropic glutamate and GABA_B receptors and the potential to target receptor subunits for future therapeutic intervention in neurological and mental health disorders.

Jean-Philippe Pin
& Bernhard Bettler

Brief Communications Arising | 30 November 2016

Drug response consistency in CCLE and CGP

Mehdi Bouhaddou
, Matthew S. DiStefano
& Marc R. Birtwistle

Brief Communications Arising | 30 November 2016

Safikhani et al. reply

Zhaleh Safikhani
, Nehme El-Hachem
& Benjamin Haibe-Kains

Inside View | 23 November 2016

Inside View: Almirall

Letter | 16 November 2016

High-resolution crystal structure of the human CB1 cannabinoid receptor

The authors report a 2.6 Å resolution crystal structure of the human CB1 cannabinoid receptor trapped in the inactive conformation and bound to the antagonist taranabant.

Zhenhua Shao
, Jie Yin
& Daniel M. Rosenbaum

Letter | 13 July 2016

Allosteric nanobodies reveal the dynamic range and diverse mechanisms of G-protein-coupled receptor activation

Stabilization of an active and inactive conformation of the β₂-adrenergic receptor by allosteric nanobodies reveals differential ligand-dependent regulation of receptor states to control G-protein-coupled receptor activation.

Dean P. Staus
, Ryan T. Strachan
& Robert J. Lefkowitz

Article | 04 May 2016

NMDAR inhibition-independent antidepressant actions of ketamine metabolites

The metabolism of ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and the (2R,6R)-HNK enantiomer lacks ketamine-related side effects but exerts rapid and sustained antidepressant actions in mice; these antidepressant effects are independent of NMDAR inhibition but require AMPAR activity.

Panos Zanos
, Ruin Moaddel
& Todd D. Gould

Letter | 24 February 2016

Structural basis of lenalidomide-induced CK1α degradation by the CRL4^CRBN ubiquitin ligase

Thalidomide and its derivative lenalidomide bind the CRL4^CRBN E3 ubiquitin ligase and target protein substrates for degradation; structural and functional data determined here show that casein kinase 1α and the lymphoid transcription factor Ikaros, the efficacy targets of lenalidomide in two different blood cancers, interact with the CRBN–lenalidomide interface through a β-hairpin destruction motif.

Georg Petzold
, Eric S. Fischer
& Nicolas H. Thomä

Letter | 04 November 2015

Resensitizing daclatasvir-resistant hepatitis C variants by allosteric modulation of NS5A

The drug daclatasvir (DCV), which inhibits the hepatitis C virus (HCV) non-structural protein 5A (NS5A), can successfully reduce viral load in patients; here, a combination of DCV and an NS5A analogue is shown to enhance DCV potency on multiple genotypes and overcome resistance in vitro and in a mouse model.

Jin-Hua Sun
, Donald R. O’Boyle II
& Min Gao

Spotlight | 18 June 2014

Spotlight on Biotech/Pharma

Letter | 13 November 2013

Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors

Two small-molecule disruptors of the glucokinase–glucokinase-regulatory-protein complex, AMG-1694 and AMG-3969, are identified that decrease blood glucose levels in various models of hyperglycaemic rodents.

David J. Lloyd
, David J. St Jean Jr
& Clarence Hale

Article | 12 December 2012

Automated design of ligands to polypharmacological profiles

An automated approach designing drug ligands to multi-target profiles (with a 75% prediction success rate) is experimentally validated by the invention of novel ligands tailored to the complex and physiologically-relevant goal of identifying drugs that can specifically target profiles of multiple proteins.

Jérémy Besnard
, Gian Filippo Ruda
& Andrew L. Hopkins

Article | 09 December 2012

High-resolution crystal structure of human protease-activated receptor 1

The X-ray crystal structure of the human G-protein-coupled receptor protease-activated receptor 1 (PAR1) bound to the antagonist vorapaxar is solved, revealing an unusual method of drug binding that should facilitate the development of improved PAR1-selective antagonists.