Stabilised G protein-coupled receptors in structure-based drug design: a case study with adenosine A2A receptor

MedChemComm ◽  
2013 ◽  
Vol 4 (1) ◽  
pp. 52-67 ◽  
Author(s):  
Stephen P. Andrews ◽  
Benjamin Tehan
Keyword(s):  
Parkinson’S Disease ◽  
Drug Design ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Adenosine A2a Receptor ◽  
Structure Based Drug Design ◽  
A2a Receptor ◽  
Adenosine A2a ◽  
G Protein Coupled

The first example of structure-based drug design with stabilised GPCRs has enabled the identification of a preclinical candidate for the treatment of Parkinson's disease.

Structure-based drug design of chromone antagonists of the adenosine A2A receptor

MedChemComm ◽  
2014 ◽  
Vol 5 (5) ◽  
pp. 571-575 ◽  
Author(s):  
Stephen P. Andrews ◽  
Jonathan S. Mason ◽  
Edward Hurrell ◽  
Miles Congreve
Keyword(s):  
Drug Design ◽  
Adenosine A2a Receptor ◽  
Structure Based Drug Design ◽  
A2a Receptor ◽  
Adenosine A2a

Structure-based drug design identifies potent & selective GPCR antagonists.

scholarly journals Progress in Structure Based Drug Design for G Protein-Coupled Receptors

2011 ◽  
Vol 54 (13) ◽  
pp. 4283-4311 ◽  
Author(s):  
Miles Congreve ◽  
Christopher J. Langmead ◽  
Jonathan S. Mason ◽  
Fiona H. Marshall
Keyword(s):  
Drug Design ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Structure Based Drug Design ◽  
G Protein Coupled

scholarly journals Toward G protein-coupled receptor structure-based drug design using X-ray lasers

IUCrJ ◽  
2019 ◽  
Vol 6 (6) ◽  
pp. 1106-1119 ◽  
Author(s):  
Andrii Ishchenko ◽  
Benjamin Stauch ◽  
Gye Won Han ◽  
Alexander Batyuk ◽  
Anna Shiriaeva ◽  
...  
Keyword(s):  
Drug Design ◽  
Crystal Structures ◽  
G Protein ◽  
Rapid Determination ◽  
Binding Pocket ◽  
G Protein Coupled Receptors ◽  
Structure Based Drug Design ◽  
G Protein Coupled ◽  
Serial Femtosecond Crystallography

Rational structure-based drug design (SBDD) relies on the availability of a large number of co-crystal structures to map the ligand-binding pocket of the target protein and use this information for lead-compound optimization via an iterative process. While SBDD has proven successful for many drug-discovery projects, its application to G protein-coupled receptors (GPCRs) has been limited owing to extreme difficulties with their crystallization. Here, a method is presented for the rapid determination of multiple co-crystal structures for a target GPCR in complex with various ligands, taking advantage of the serial femtosecond crystallography approach, which obviates the need for large crystals and requires only submilligram quantities of purified protein. The method was applied to the human β2-adrenergic receptor, resulting in eight room-temperature co-crystal structures with six different ligands, including previously unreported structures with carvedilol and propranolol. The generality of the proposed method was tested with three other receptors. This approach has the potential to enable SBDD for GPCRs and other difficult-to-crystallize membrane proteins.

scholarly journals Cryo-EM structure of the adenosine A2A receptor coupled to an engineered heterotrimeric G protein

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Javier García-Nafría ◽  
Yang Lee ◽  
Xiaochen Bai ◽  
Byron Carpenter ◽  
Christopher G Tate
Keyword(s):  
G Protein ◽  
Binding Pocket ◽  
Adenosine A2a Receptor ◽  
Intracellular Loop ◽  
Heterotrimeric G Protein ◽  
A2a Receptor ◽  
Density Map ◽  
Adenosine A2a ◽  
G Protein Coupled ◽  
Comparable Quality

The adenosine A2A receptor (A2AR) is a prototypical G protein-coupled receptor (GPCR) that couples to the heterotrimeric G protein GS. Here, we determine the structure by electron cryo-microscopy (cryo-EM) of A2AR at pH 7.5 bound to the small molecule agonist NECA and coupled to an engineered heterotrimeric G protein, which contains mini-GS, the βγ subunits and nanobody Nb35. Most regions of the complex have a resolution of ~3.8 Å or better. Comparison with the 3.4 Å resolution crystal structure shows that the receptor and mini-GS are virtually identical and that the density of the side chains and ligand are of comparable quality. However, the cryo-EM density map also indicates regions that are flexible in comparison to the crystal structures, which unexpectedly includes regions in the ligand binding pocket. In addition, an interaction between intracellular loop 1 of the receptor and the β subunit of the G protein was observed.

scholarly journals Engineering of Challenging G Protein-Coupled Receptors for Structure Determination and Biophysical Studies

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1465
Author(s):  
Yann Waltenspühl ◽  
Janosch Ehrenmann ◽  
Christoph Klenk ◽  
Andreas Plückthun
Keyword(s):  
High Resolution ◽  
Drug Design ◽  
G Protein ◽  
Drug Targets ◽  
Native Mass Spectrometry ◽  
G Protein Coupled Receptors ◽  
Resonance Spectroscopy ◽  
Structure Based Drug Design ◽  
Biophysical Studies ◽  
G Protein Coupled

Membrane proteins such as G protein-coupled receptors (GPCRs) exert fundamental biological functions and are involved in a multitude of physiological responses, making these receptors ideal drug targets. Drug discovery programs targeting GPCRs have been greatly facilitated by the emergence of high-resolution structures and the resulting opportunities to identify new chemical entities through structure-based drug design. To enable the determination of high-resolution structures of GPCRs, most receptors have to be engineered to overcome intrinsic hurdles such as their poor stability and low expression levels. In recent years, multiple engineering approaches have been developed to specifically address the technical difficulties of working with GPCRs, which are now beginning to make more challenging receptors accessible to detailed studies. Importantly, successfully engineered GPCRs are not only valuable in X-ray crystallography, but further enable biophysical studies with nuclear magnetic resonance spectroscopy, surface plasmon resonance, native mass spectrometry, and fluorescence anisotropy measurements, all of which are important for the detailed mechanistic understanding, which is the prerequisite for successful drug design. Here, we summarize engineering strategies based on directed evolution to reduce workload and enable biophysical experiments of particularly challenging GPCRs.

Novel Insights into Biased Agonism at G Protein-Coupled Receptors and their Potential for Drug Design

2013 ◽  
Vol 19 (28) ◽  
pp. 5156-5166 ◽  
Author(s):  
Maria Marti-Solano ◽  
Ramon Guixa-Gonzalez ◽  
Ferran Sanz ◽  
Manuel Pastor ◽  
Jana Selent
Keyword(s):  
Drug Design ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Biased Agonism ◽  
G Protein Coupled
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