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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

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