Cardiovasular Pharmacology Tutorial using CHIME
Renin-Angiotensin System Stucture-Function relationships
Neurotransmitters and hormones act by binding to specific protein targets, usually cell surface receptors. They bind to a specific site on these proteins, through a "lock and key" style interaction, i.e. the shape of the molecule fits a complementary pocket in the receptor. This is only an approximation, as both the neurotransmitter molecules themselves and the protein are somewhat flexible, and electrostatic and polar interactions are important as well, but provides a useful mental image for imagining ligand (neurotransmitter/drug) receptor interaction.
Neurotransmitters and hormones act by producing changes in the conformation of the receptor they bind to, this conformational change leads to activation of signal transduction pathways either directly or, in the case of the adrenoceptors, indirectly (via G-proteins). In the case of angiotensin receptors, these proteins have seven transmembrane domain spanning helicies (numbered I-VII), which aggregate together into a rough cylinder with a pore in the centre. Angotensin binds on the inside of this pore. [Go to 3D model]
Angiotensin AT1 receptor
This panel shows the angiotensin II AT1 receptor in cartoon mode, with some of the loops connecting the helices omitted for clarity. This 3D structure is a model based on the rhodopsin receptor to guide folding of the AT1-receptor sequence. The view is from above the molecule looking down into the pore, in roughly the same orientation as the b2-adrenoceptor. Use the buttons to highlight various parts of the molecule that are important for function. Click the button again to clear your selection.
In the case of the angiotensin AT1-receptor shown above, for both angiotensin II and and angiotensin III the C-terminal phenylalanine binds to the lysine residue at position 199 on helix IV. Histidine 256 forms a pi bond with the phenylalanine ring stabilizing it. The positively charge amine group on arginine2 of AII (Arg1 of AIII) binds to negatively charged carboxylic acid of aspartate 281 on helix VII. This interaction is essential for agonism. The side-chain of tyrosine4 of Ang II forms an aminoľaromatic interaction with
asparagine 111 on helix III and is important for binding and serves as a key step for receptor activation. The positively charged histidine 183 on the loop connecting helicies IV and V interacts with the carboxyl group of aspartate1 of AII but plays no role in AIII binding and agonism (see Hunyady et al., (2003) Agonist induction and conformational selection during activation of a G-protein-coupled receptor. TIPS 24, 81-86).
A similar situation is seen for the AT2 receptor, the critical binding residues are:
D(Asp 281) N(Asn 111) K(Lys 199) H(His 256) AT1
D(Asp 297) N(Asn 126) K(Lys 215) H(His 273) AT2
The following table allows you to further explore the structure of angiotensin II as it relates to agonist activity. [Go to structural model]
This panel shows angiotensin II in stick mode, use the buttons to highlight various parts of the molecule that are important for function. Click the button again to clear your selection.
As we saw in the adrenergic tutorial, drugs act by mimicking the structure of the natural neurotransmitter and hormones. There may be an almost direct structural correspondence between the drug and hormone (e.g. saralasin) or the structures may be superficially quite different (e.g. losartan and adrenaline), but the drugs shape and electrostatic charge distribution mimics the shape and charge of the natural compound. Whether a drug is an agonist or antagonist depends on a number of structural issues. Replacing or removing the Arg2 of angiotensin II makes it likely that the resulting peptide will be a partial agonist or antagonist. In the case of Losartan, this drug has been designed to mimic the C-terminal end of angiotensin II, and lacks any interaction with either histidine 183 or aspartate 281, and act as a potent antagonist. In the case of saralasin, [Sar1, Val5, Ala8] Angiotensin II, aspartate has been replaced by sarcosine, and phenylalanine by alanine. Although the critical arginine has been retained, the orientation is such that contact is much reduced, and saralasin is a weak partial agonist, that acts as a functional antagonist.
Comparison of binding of angiotensin (left hand panel) and the antagonist losartan (Right hand panel) to the AT1 receptor. We are looking down on the receptor from the top. Circles represent transmembrane helicies . Some transmembrane helicies have been omitted for clarity. Left panel, Binding of Angiotensin II to the AT1 receptor, the N terminal region of angiotensin is represented by R for simplicity. The D(Asp 281) N(Asn 111) K(Lys 199) H(His 256) binding sequence is shown in RED (as for figure 2), other amino acids that are peripherally related in stabilizing the molecule are shown in BLACK. Right panel: Binding of the ligand losartan to the AT1 receptor. The common binding sequence between AII and losartan is shown in BLUE, other amino acids that are peripherally related in stabilizing the molecule are shown in BLACK. Note that different amino acids are involved in losartan binding.
The following table allows you to explore these features in more detail. [Go to 3D overlays]
[go to top] [Starting page] [adrenergic drugs][cholinergic drugs]
Structures are either from the Structure
Data Base of the Department of Structural Organic Chemistry, Tokyo University of Pharmacy and Life Science or drawn by Dr. Musgrave. Visualisation is through the MDL CHIME plug-in. This page produced by Dr.
Ian Musgrave of the Department of Clinical and Experimental Pharmacology, University of Adelaide.