The structural study of mutation-induced inactivation of human muscarinic receptor M4

IUCrJ
Jingjing WangTian Hua

Abstract

Human muscarinic receptor M4 belongs to the class A subfamily of the G-protein-coupled receptors (GPCRs). M4 has emerged as an attractive drug target for the treatment of Alzheimer's disease and schizophrenia. Recent results showed that M4-mediated cholinergic transmission is related to motor symptoms in Parkinson's disease. Selective ligand design for the five muscarinic acetylcholine receptor (mAchR) subtypes currently remains challenging owing to the high sequence and structural similarity of their orthosteric binding pockets. In order to obtain M4-selective antagonists, a new approach was tried to lock M4 into an inactive form by rationally designing an N4497.49R mutation, which mimics the allosteric sodium binding in the conserved sodium site usually found in class A GPCRs. In addition, the crystal structure of the mutation-induced inactive M4 was determined. By comparative analysis with other mAchR structures, followed by functional assays, the N4497.49R mutation was shown to stabilize M4 into an inactive state. Virtual screening of a focused ligand library using the crystal structure showed that the inactive M4 prefers antagonists much more than agonists. This study provides a powerful mutation strategy to stabilize GPCR...Continue Reading

References

Jan 1, 1990·Annual Review of Pharmacology and Toxicology·E C HulmeN J Buckley
Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Jun 2, 2005·Journal of Chemical Neuroanatomy·Teresa Marie du BoisXu-Feng Huang
Nov 28, 2006·Circulation Journal : Official Journal of the Japanese Circulation Society·Mahoto KatoMasafumi Kitakaze
Mar 13, 2008·Structure·Alexander I AlexandrovRaymond C Stevens
Mar 21, 2008·Journal of Computational Chemistry·Sunhwan JoWonpil Im
Aug 6, 2008·Proceedings of the National Academy of Sciences of the United States of America·W Y ChanC C Felder
Apr 25, 2009·Nature Protocols·Martin Caffrey, Vadim Cherezov
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Jan 9, 2010·Acta Crystallographica. Section D, Biological Crystallography·Vincent B ChenDavid C Richardson
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Wolfgang Kabsch
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Martyn D WinnKeith S Wilson
Sep 6, 2011·Nucleic Acids Research·Mikhail A LomizeAndrei L Lomize
Jan 10, 2012·Handbook of Experimental Pharmacology·Richard M Eglen
Feb 24, 2012·Nature·Andrew C KruseBrian K Kobilka
Apr 17, 2012·Acta Crystallographica. Section D, Biological Crystallography·Oliver S SmartGérard Bricogne
May 26, 2012·Science·P Andrew Karplus, Kay Diederichs
Jul 17, 2012·Science·Wei LiuRaymond C Stevens
Dec 12, 2012·Nature·Cheng ZhangBrian K Kobilka
Nov 22, 2013·Nature·Andrew C KruseBrian K Kobilka
Jan 15, 2014·Nature·Gustavo FenaltiRaymond C Stevens
Apr 29, 2014·Trends in Biochemical Sciences·Vsevolod KatritchRaymond C Stevens
Feb 24, 2015·Progress in Neurobiology·K L Eskow JaunarajsA Pisani
Aug 8, 2015·Nature·Weijiao HuangBrian K Kobilka
Nov 18, 2015·Journal of Chemical Theory and Computation·James A MaierCarlos Simmerling
Jul 9, 2013·Journal of Chemical Theory and Computation·Daniel R Roe, Thomas E Cheatham
Mar 8, 2016·Nature Structural & Molecular Biology·Jie YinDaniel M Rosenbaum
Mar 10, 2016·Nature·David M ThalArthur Christopoulos
Sep 2, 2016·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Samira ZtaouMarianne Amalric
Dec 19, 2017·Structure·Owen N VickeryUlrich Zachariae
Sep 8, 2018·The Journal of General Physiology·Wessel A C BurgerDavid M Thal
Nov 9, 2018·Proceedings of the National Academy of Sciences of the United States of America·Hongtao LiuPeter Gmeiner
Nov 14, 2018·Nature Chemical Biology·Ryoji SunoTakuya Kobayashi
Mar 26, 2019·Current Opinion in Structural Biology·Petr PopovVsevolod Katritch
Jun 22, 2019·ACS Medicinal Chemistry Letters·Qingyi YangLei Zhang
Oct 8, 2019·Acta Crystallographica. Section D, Structural Biology·Dorothee LiebschnerPaul D Adams

❮ Previous
Next ❯

Citations

May 1, 2021·Scientific Reports·Rabindra V ShivnaraineJohn Ellis

❮ Previous
Next ❯

Methods Mentioned

BETA
PCR
size-exclusion chromatography
biosensor
X-ray

Software Mentioned

Visual Molecular Dynamics ( VMD
Protein Preparation Wizard
CCP
PMEMD
Schrödinger
Phaser
Phenix
- GUI Membrane Builder
Schrödinger Suite
XDS

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.