PSI Structural Biology Knowledgebase

PSI | Structural Biology Knowledgebase
Header Icons

Related Articles
Drug Discovery: Solving the Structure of an Anti-hypertension Drug Target
July 2015
Retrospective: 7,000 Structures Closer to Understanding Biology
July 2015
Design and Evolution: Bespoke Design of Repeat Proteins
June 2015
Design and Evolution: Tunable Antibody Binders
June 2015
Immunity: Clustering Immunoglobulins
June 2014
Immunity: Conformational Capture
June 2014
Immunity: One Antibody to Rule Them All
June 2014
Immunity: Tissue Contribution
June 2014
Caught in the Act
December 2013
Serum Albumins and Allergies
October 2013
The Immune System: A Brotherhood of Immunoglobulins
June 2013
The Immune System: A Strong Competitor
June 2013
The Immune System: Strand Swapping for T-Cell Inhibition
June 2013
The Immune System: Super Cytokines
June 2013
Tuning Immune Response with Costimulation
June 2013
Regulatory insights
September 2012
Serum albumin diversity
August 2012
Substrate specificity sleuths
April 2012
February 2012
Analyzing an allergen
January 2012
TLR4 regulation: heads or tails?
October 2011
Binding complement with complementarity
June 2011

Research Themes Immunology

Drug Discovery: Solving the Structure of an Anti-hypertension Drug Target

SBKB [doi:10.1038/sbkb.2015.22]
Featured Article - July 2015
Short description: Serial femtosecond crystallography is used to solve the structure of angiotensin II type 1 receptor.

The structure of human AT1R bound to an antagonist is solved using serial femtosecond crystallography with X-ray free-electron laser. Reprinted from ref. 1, permission granted by Elsevier, 2015.

Cardiovascular disease is one of the leading causes of death worldwide, and has therefore been the focus of considerable effort and advances in drug discovery. Hypertension is the main risk factor for cardiovascular disease, and the G protein-coupled receptor (GPCR) angiotensin II type 1 receptor (AT1R) is an important target for anti-hypertensive drugs, known as AT1R blockers or ARBs. However, the lack of structural data for how ARBs bind AT1R has hampered development and rational optimization of these drugs.

Now Cherezov and colleagues (PSI GPCR Network and MPID) have taken advantage of new methodology to elucidate the structure of AT1R, an achievement previously prevented by the size of the crystals formed by this protein, which are exceedingly small. Luckily, this is not a problem when using the serial femtosecond crystallography technique, which allowed solving the structure of AT1R (PDB 4YAY) to a resolution of 2.9 Å, using crystals that were only 10 × 2 × 2 μm in size. Over 70,000 indexed protein crystal patterns were needed to solve the structure, collected using synchrotron radiation focused on tiny crystals grown in a matrix that mimics the cell membrane.

Overall, the structure of the protein is similar to other peptide-binding GPCRs, including chemokine receptors and opioid receptors. Perhaps more interestingly, the structure was solved with an ARB (ZD7155) bound in the ligand-binding pocket, and most of the important residues for this interaction are not conserved in other GPCRs. Thus, the ligand-binding pocket is unique and requires specific inhibitors.

Molecular modelling of other ARBs into the ligand-binding site of AT1R showed that most compounds bound in similar orientations. These interactions should now be the starting point for structure-based drug design and, hopefully, more effective and specific anti-hypertension agents.

Rebecca Kirk


  1. H. Zhang et al. Structure of the angiotensin receptor revealed by serial femtosecond crystallography.
    Cell. 161, 833-844 (2015). doi:10.1016/j.cell.2015.04.011

Structural Biology Knowledgebase ISSN: 1758-1338
Funded by a grant from the National Institute of General Medical Sciences of the National Institutes of Health