Corporate Banner
Satellite Banner
Crystallography
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

New Insights for Drug Design from the X-ray Crystallographic Structures of GPCRs

Published: Wednesday, July 18, 2012
Last Updated: Wednesday, July 18, 2012
Bookmark and Share
This study looks at recent developments in high-resolution imaging of GPCR structures and conformational changes upon activation, and how this knowledge can help in the design of potent drugs.

Abstract

Methodological advances in X-ray crystallography have made possible the recent solution of X-ray structures of pharmaceutically important G protein-coupled receptors (GPCRs), including receptors for biogenic amines, peptides, a nucleoside and a sphingolipid. These high-resolution structures have greatly increased our understanding of ligand recognition and receptor activation. Conformational changes associated with activation common to several receptors entail outward movements of the intracellular side of transmembrane helix 6 (TM6) and movements of TM5 toward TM6. Movements associated with specific agonists or receptors have also been described, e.g. extracellular loop 3 (EL3) in the A(2A) adenosine receptor. The binding sites of different receptors partly overlap but differ significantly in ligand orientation, depth and breadth of contact areas in TM regions, and the involvement of the ELs. A current challenge is how to utilize this structural information for the rational design of novel potent and selective ligands. For example, new chemotypes were discovered as antagonists of various GPCRs by subjecting chemical libraries to in silico docking in the X-ray structures. The vast majority of GPCR structures and their ligand complexes are still unsolved, and no structures are known outside of Family A GPCRs. Molecular modeling, informed by supporting information from site-directed mutagenesis and structure activity relationships, has been validated as a useful tool to extend structural insights to related GPCRs and to analyze docking of other ligands in already crystallized GPCRs.

This study is published online in Molecular Pharmacology and is free to access.


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 3,300+ scientific posters on ePosters
  • More than 4,900+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

X-Ray Free Electron Laser for Fixed-Target Protein Serial Microcrystallography
The article presents the first proof-of-principle results from fixed-target serial crystallography using the Linac Coherent Light Source.
Monday, October 06, 2014
Identifying, Studying and Making Good Use of Macromolecular Crystals
Techniques that extend the observation of crystals beyond the optical microscope will enhance structural biology in the future.
Monday, October 06, 2014
Mosquitoes Resistant to DDT Also Resistant to Mosquito Net Insecticide
Understanding how resistance works will help to develop tests, stopping resistance genes from spreading amongst mosquito populations.
Thursday, February 27, 2014
Defining the Communication Between Agonist and Coactivator Binding in the Retinoid X Receptor a Ligand Binding Domain
The four structural changes are conserved in all x-ray structures of the RXR ligand binding domain in the presence of agonist and coactivator peptide.
Wednesday, November 06, 2013
The Structure of Classical Swine Fever Virus Npro
This study reports the crystal structures of CSFV Npro and a C168A cleavage site Npro mutant to 1.6 Å resolution.
Friday, October 25, 2013
EphA5 Ligand Binding Specificity as Revealed by X-ray Crystallography, NMR and MD Simulations
This study reveals that the EphA5 LBD has dynamic properties very different from those of the EphA4 LBD, despite the 74% sequence identity and structural similarity.
Monday, October 07, 2013
3.5Å cryoEM Structure of Hepatitis B Virus Core Assembled from Full-Length Core Protein
Hepatitis B virus (HBV) infection results in over a million deaths worldwide each year.
Tuesday, September 24, 2013
Two Pfam Protein Families Characterized by a Crystal Structure of Protein lpg2210
NIH centers are systematically targeting uncharacterized proteins with the goal of providing structural information for a significant portion of the protein universe.
Monday, September 09, 2013
Structural Insights into the Functions of the FANCM-FAAP24 Complex in DNA Repair
This study reports the crystal structure of human FANCM-FAAP24 complex, which together with the biological data provide the molecular insights into its functions in DNA repair.
Monday, September 09, 2013
Structural Insights into Central Hypertension Regulation by Human Aminopeptidase A
This study determined the crystal structures of APA complexed with different ligands and calcium.
Wednesday, July 31, 2013
The Serine Protease Domain of MASP-3: Enzymatic Properties and Crystal Structure in Complex with Ecotin
A tetrameric complex comprising an ecotin dimer and two MASP-3 SP domains was isolated and its crystal structure was solved.
Monday, July 22, 2013
Crystal Structure of a GroEL-ADP Complex in the Relaxed Allosteric State
Conformational states are shown to exist as a structurally heterogeneous ensemble within a single ring.
Monday, July 22, 2013
Crystal Structure of Signal Regulatory Protein Gamma in Complex with an Antibody Fab Fragment
This paper presents the X-ray crystal structure of the complete extracellular portion of SIRP? co-crystallized with the Fab fragment of the OX117 monoclonal antibody.
Tuesday, July 09, 2013
The X-ray Crystal Structure of Mannose-Binding Lectin-Associated Serine Proteinase-3
These data reveal substantial perturbation of the active site, consistent with a correlation between the lack of MASP-3 function and the 3MC syndrome.
Thursday, June 27, 2013
Crystal Structure of a Human IaB Kinase ß Asymmetric Dimer
The observed domain movements in the structures of IKK may represent transphosphorylation steps that accompany IKK activation.
Thursday, June 27, 2013
Scientific News
Mechanisms of Calcium Blockers
Researchers describe how the fundamental mode of action of two distinct chemical classes of calcium channel blockers differs.
Catching Proteins in the Act
Scientists can now observe light activated processes in proteins through the use of free-electron x-ray lasers.
'Missing Evolutionary Link' of Natural Drug Source Found
Scripps Florida study finds 'missing evolutionary link' of a widely used natural drug source
New Way of Displaying 3D Molecular Structures
Metal-organic frameworks provide a new platform for solving the structure of hard-to-study samples.
How Cloud Connectivity Can Combat the Reproducibility Crisis
This infographic explains the reproducibility crisis, and how cloud connectivity can help overcome this problem.
Blocking the Waste Disposal Unit
Detailed structure paves the way for more effective cancer therapies.
Massive Helium Discovery a "Game Changer" for Medical Industry
A new development is gas exploration has yielded the discovery of a huge helium gas field, which could help relieve the dwindling supply.
Diamond Light Source Use Quorum Cryo-SEM Preparation System in New Beamline
Quorum Technologies report on the use of their PP3000T cryo preparation system in conjunction with the new beamline development at Diamond Light Source
Anticancer Drug Stops Ebola Virus Molecule in its Tracks
A team of scientists from the University of Oxford have successfully mapped the structure of the Ebola virus molecule that drives the attack strategy and leads to fatal infections in humans.
Molecular Map Provides Clues To Zinc-Related Diseases
Mapping the molecular structure where medicine goes to work is a crucial step toward drug discovery against deadly diseases.
SELECTBIO

SELECTBIO Market Reports
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
3,300+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,900+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!