Angiotensin II (Ang II) ()is a key hormone that influences blood pressure regulation. Two distinct classes of Ang II receptors, AT and AT, mediate its function(1, 2) . The AT receptor is responsible for mediating the potent vasoconstrictor effect of Ang II. Therefore, the AT receptor is a major target for drug design in the treatment of hypertension, congestive heart failure, and cardiac hypertrophy(1) . Previous structure-activity evaluation has demonstrated that the Phe side chain and the -carboxyl group of Ang II are critical determinants of angiotensin's biological potency(2) . Several non-peptide agonists and antagonists of the AT receptor also preserve an acidic group attached to an aromatic function, suggesting that it is a crucial determinant of ligand specificity(1) .

The binding pocket of the AT receptor for various ligands is not clearly defined. The structural model of the AT receptor contains seven transmembrane -helices with three interhelical loops on either side of the membrane. Structure-function studies of the AT receptor so far have indicated that the carboxyl terminus of Ang II and the non-peptide ligands bind within the transmembrane domain(3, 4, 5, 6, 7, 8, 9, 10, 11) , but the binding of Ang II and other peptide analogues may also be influenced by the extracellular domain of the receptor(3, 4, 5, 6, 7, 8, 9, 10, 11) . To identify points of interaction that are common to both peptide and non-peptide ligands on the AT receptor, we defined the subsite for binding the acidic pharmacophore that is present on all ligands(9) . We showed that the carboxyl group of Ang II, tetrazole, and sulfonylamide groups of non-peptide antagonists bind to the -amino group of Lys in the fifth transmembrane helix of the AT receptor. The role of this ion pair in the activation of AT receptor function is not clearly established. Aumelas et al.(12) showed that the -COOH group stabilizes the conformation of the Phe side chain in Ang II. Therefore, the interaction of Lys with the -COOH group of Ang II is likely very important for positioning the Phe within the pocket of the AT receptor. Molecular modelling studies indicate that Phe of Ang II might interact with His among other candidate residues. ()The functional role of His is not demonstrated as yet. Therefore, we investigated the following questions. Is the ion-pair interaction between Lys and -COOH of Ang II essential for the function of the receptor? What is the role of His in the AT receptor function? The results demonstrate that the ion-pair interaction of Ang II and Lys is not essential for receptor activation and that His plays an important role in receptor activation because it directly interacts with the Phe side chain of the ligand.

EXPERIMENTAL PROCEDURES

Materials

Mutagenesis and Expression

Inositol Phosphate (IP) Measurements

RESULTS

Stimulation of IP Production by the AT Receptor

Figure 1: Inositol phosphate production in COS-1 cells expressing wild-type and various mutants of the rat AT receptor gene. Basal, shown as an open box, is the IP production in transfected cells without stimulation by [Sar]Ang II and the filled box is with stimulation by 10M [Sar]Ang II. The concentration of other ligands are 10M Ang II, 10ML-162,313, 10M DUP753. The values represent mean ± S.E. of three or more independent transfection experiments performed in duplicate for each mutant. The level of expression of each of the mutant receptor proteins was within 3-fold of the wild-type receptor expression. The B values estimated per mg of total membrane protein are as follows: wild type, 5.2 ± 0.2 pmol; K199Q, 2.8 ± 0.4; K199A, 2.4 ± 0.2; H256Q, 2.1 ± 0.5; H256A, 4.3 ± 0.2.

The concentration dependence (EC = 2 ± 0.1 nM) and level of stimulation (3- to 5-fold over the basal) of IP formation were similar to the previously reported characteristics of AT receptor in the transfected COS-1 cells (Fig. 2; (8) and (10) ). [Sar]Ang II-amide (EC of 73 ± 4 nM) produced nearly the same maximal level of response, although its affinity for the wild-type AT receptor is 10-fold lower. Since [Sar]Ang II-amide could be converted to [Sar]Ang II because of spontaneous deamidation, fresh stock solutions were used each time. The molecular weight of the peptide in the assayed stock solution was confirmed by mass spectrometry. The antagonist [Sar,Ile]Ang II (EC = 1.5 ± 0.3 nM) produced <20% of the maximal [Sar]Ang II response. The maximal response to stimulation with the non-peptide agonist L-162,313 was 40 ± 5% of the [Sar]Ang II response with an EC of 98 ± 26 nM, as reported earlier(8, 10) . L-162,313 bound to wild-type receptors with an affinity of 14 ± 3 nM (Fig. 2).

Figure 2: Relative potency of agonists to activate the inositol phosphate production in COS-1 cells transfected with wild-type AT receptor gene. IP accumulation (mean ± S.E.) is expressed as percentage of specific IP accumulation after stimulation with 10M [Sar]Ang II. The ligand concentration stimulating 50% of the maximal response calculated are as follows: [Sar]Ang II, 2 ± 0.1 nM; [Sar,Ile], 1.5 ± 0.3 nM; [Sar]Ang II-amide, 73 ± 4 nM; and the non-peptide L-162,313, 98 ± 26 nM. 10M DUP does not inhibit basal IP production in the untransfected COS-1 cells.

Stimulation of IP Production by AT Receptor Mutants

Figure 3: The agonist stimulation of the mutant AT receptors by [Sar]Ang II (A-C) and the non-peptide, L-162,313 (D). The IP produced in each case is represented as the percentage of maximum response for the wild-type AT receptor in parallel experiments under identical conditions. The values (mean ± S.E.) are from three independent experiments.

The receptor activation seems to be influenced by the kind of side chain at position 256. In the H256A and H256Q mutants, the maximal response produced is 20-40% of that for the wild-type (Fig. 3B). The EC for this diminished response is 1.8 nM for H256Q and 5.4 nM for H256A. The affinity of [Sar]Ang II to both the mutants (0.6 nM and 0.8 nM) is nearly identical with that of the wild-type AT receptor (see (9) ). The mutant H256R, K199A/H256A, and K199A/H256R receptors were completely defective, although they bound [Sar]Ang II with high affinity (K = 0.8 nM, 3.9 nM, and 1.6 nM, respectively) (Fig. 3C and (9) ).

As shown in Fig. 3D, the K199Q mutant is not stimulated by the non-peptide agonist L-162,313. This mutation caused an approximate 7-fold decrease of L-162,313 binding affinity (103 ± 8 nM). The stimulation of H256Q and the H256A mutants was diminished, respectively, to 10 ± 5% and 18 ± 10% of the wild-type receptor stimulation. The K of L-162,313 to mutants is 110 ± 11 nM for H256Q and 191 ± 14 nM for H256A mutants.

Influence of Modification of Phe Side Chain of Ang II on the Properties of Wild-type, H256Q, and H256A Receptors

Figure 4: Influence of modification of Phe side chain of Ang II on interaction with wild-type and His mutants. A, relative changes in the affinity of wild-type and the mutant H256A AT receptor toward analogues of Ang II carrying modification of the Phe side chain. The values represent (mean ± S.E.) K/K of two to four independent determinations. B, inositol phosphate production in response to various analogues in transfected COS-1 cells containing matched receptor density.

In the H256A mutant, the affinity loss is larger for Ala and Thr side chains at position 8 of the Ang II than with wild-type AT receptor. However, the affinity of the H256A mutant was increased toward the [Trp]Ang II analogue in contrast to a decrease of affinity of wild-type receptor (Fig. 4A). However, the [Trp]Ang II-stimulated IP responses from H256Q and H256A mutants were approximately 40% of that from the wild-type AT receptor (Fig. 4B).

DISCUSSION

The Phe side chain of Ang II plays a crucial role in the activation of the AT receptor(1, 2) . Because several weak interactions may collectively bind the Phe side chain, mutation-induced loss of affinity may be difficult to measure. Thus, it was anticipated that the Phe binding site would be difficult to locate. We approached this problem by initially identifying the docking residues for the Arg and the -COOH group of Ang II(9, 10) . A molecular model based on Ang II docked to Lys and Asp predicted several potential sites for the interaction of the Phe side chain. Since replacement of the Phe side chain of Ang II with aliphatic side chains such as Ile, Ala, and Thr produces poor agonists without substantial change of affinity, the replacement of the complementary interacting residue must also produce a functionally defective receptor with no change in affinity for Ang II. Furthermore, the Phe side chain docking site is likely to be proximal to Lys because it binds the -COOH group of Phe. Topological location and the functional defect caused by the His mutations are consistent with this expectation.

The H256Q and H256A mutants cause only small changes in agonist affinity, but a substantial defect in IP response (Fig. 3B). As shown in Fig. 4A, reduction of the size of the His side chain correlates with a change of binding affinity for position 8 analogues of Ang II. For example, the bulkier side chain of [Trp]Ang II binds better to the His Ala mutant receptor than to the His Gln mutant receptor or the wild-type receptor. The Ala, Thr, and Ile analogues of Ang II lead to weaker binding to Ala receptor than to the His and Gln receptors. Schambye et al.(11) independently observed that increase of side chain size in a H256F mutant AT receptor improves affinity for [Sar,Leu]Ang II. The van der Waals contacts between His and the angiotensin position 8 side chain appears to be a critical factor for the differences in affinity of analogues shown in Fig. 4A. This presupposes that direct contact of His with the Phe side chain is responsible for ``transmitting'' the agonist occupancy of the ligand pocket as a signal for receptor activation. Then one would expect that activation of the His Ala mutant by Ang II should be similar to the level of activation of wild-type receptor by Ala, Thr, and Ile analogues of Ang II. Inconsistency in the observed response (Fig. 3B and Fig. 4B) is most likely due to the involvement of more than one residue making contact with the Phe side chain. It is possible that several residues are involved in stabilizing the bulkier Phe side chain, as has been commonly observed in protein structures(17) . However, the interaction of Phe of Ang II with the His plays an important role in receptor activation. This cannot be explained by the simple contact between them, because substituting a Gln for His to provide isosteric hydrogen bonding properties also produced a 60% reduction of IP response. The histidine side chain has the unique protonation-tautomerism enabling it to act as a crucial bridging residue in a hydrogen-bonded network in the activated state(18) . The Gln side chain may be very inefficient in this process because it lacks tautomerism. However, the ultimate chemical basis for the function of His needs high resolution structural evidence, which is currently not available for this receptor. The most significant conclusion from the present results, therefore, is that His is a point of contact between agonists and the AT receptor where the process of receptor activation is initiated.

Because the interaction of His with Ang II provides nearly insignificant binding energy, it is important to understand how this crucial interaction is achieved. Docking the -COOH group of Phe to the Lys side chain is very important for positioning the Phe side chain of [Sar]Ang II. The modification of the Phe side chain to Ile, for example, reduces the affinity 2-fold, but modification of the -COOH group reduces the affinity of both [Sar]Ang II-amide and [Sar,Ile] Ang II-amide by 20-fold(9) . It is very likely that loss of the docking interaction will affect positioning of the Phe side chain. Therefore, the effect of Lys mutation on receptor activation may be a direct consequence of the changes in positioning the Phe side chain of [Sar]Ang II in the mutant receptors. The effects of ligand modification and complementary changes in the receptor confirm this. [Sar]Ang II-amide activated the wild-type receptor with a rightward shift of the dose-response curve with nearly the same maximal IP response as did the [Sar]Ang II. This observation is consistent with earlier bioassay results where Ang II-amide demonstrated full potency, but at a higher concentration relative to Ang II(2, 18) . The distance of interaction between Lys and the Ang II-amide compared to Ang II must remain the same, but the modification replaces an ion-pair interaction by a neutral hydrogen bond interaction. Therefore, stimulation by [Sar]Ang II does not require the negative charge of the -COOH group. When Lys is mutated to Gln, the effect is consistent with loss of charge-pair interaction and reduction of binding affinity (see (9) ). The decrease of maximal response (Fig. 3) correlates with a decrease of side chain length(17) . If the Gln side chain forms a hydrogen bond with the -COOH-group of Ang II, then one would expect that the Ala mutant receptor should be poorly activated by [Sar]Ang II. The 60% decrease in stimulation by the K199A mutant confirmed this. Basis for the defect is consistent with reduction in the volume of side chain combined with loss of hydrogen bonding ability (87 Åversus 169 Å)(17) . Therefore, we conclude that the loss of van der Waals interaction in the Gln or Ala receptors leads to the partial agonism with [Sar]Ang II stimulation, presumably due to problems with positioning the Phe side chain.

To explain the putative function of Lys and His, we propose that His interacts directly with the Phe side chain of [Sar]Ang II when the -COOH group of Phe is bound to Lys. It has been demonstrated that the rotational entropy of the Phe side chain of Ang II is restricted by its interaction with the -COOH group(12, 19) . Therefore, interaction with Lys contributes to most of the binding energy without requiring an additional contribution from the His interaction. A concerted interaction of -COOH and the side chain of Phe with the receptor may be essential for potent activation of the receptor. This suggestion needs further confirmation, although it provides an explanation for the defect in double mutants where the Arg functions as a counterion for docking the -COOH group of Ang II(9) . Because Arg is utilized only for binding the -COOH group of Ang II in the double mutant K199A/H256R, the Phe side chain cannot be positioned properly, resulting in an inactive phenotype.

The poor IP response of the two AT receptor mutants (Fig. 3) stimulated by the non-peptide agonist L-162,313 is also associated with no significant reduction of binding affinity. Since L-162,313 contains a sulfonylamide pharmacophore, it is likely to utilize Lys for docking, and His may stabilize its binding (see (9) ). Because L-162,313 has fewer contacts with the receptor, loss of any one contact may significantly affect its agonist function. Most likely, His functions as a counterion for the sulfonylamide moiety of L-162,313 in the K199A and K199Q mutants. In that configuration, L-162,313 is likely to function as an antagonist, thus explaining the complete loss of activity (see discussion on H256R mutant above, for example). The partial defect in the H256Q and H256A mutants also suggests that there might be direct interaction of His with L-162,313 that is critical for receptor activation in a fashion similar to the interaction of Ang II with His. Perlman et al.(8) have suggested that the molecular interactions of the L-162,313 may differ from both peptide and non-peptides that selectively bind to AT receptor. The results presented here suggest an overlap in the binding pocket for these two agonists, at least with regard to Lys and His, which also form the subsite for the carboxyl-terminal end of Ang II. Therefore, L-162,313 may truly be considered an analogue of the carboxyl-terminal fragment of Ang II.

It can now be argued that Lys and His make direct contacts with all classes of AT receptor-specific ligands (also discussed in (9) ). The type of interaction with these residues distinguishes agonists from antagonists. The position of His might be perturbed by antagonists and agonists differently. For example, both Lys and His interact with the tetrazole group of biphenyl antagonists, but only His may interact with the carboxyl group of imidazolyl-acrylic acid antagonists (9, 11) . Presumably, these interactions stabilize an inactive conformation of the AT receptor. The activating conformation of the receptor might require specific interaction of the acidic group with Lys and weak electrostatic interaction with His, each with considerably stringent stereospecificity. Both of these residues are conserved among all angiotensin receptors, and His corresponds to a well-defined ligand-binding residue in opsins and the amine receptors(20) . Hence, we conclude that Lys and His constitute the critical components of the ligand pocket of the AT receptor that undergoes stabilization-destabilization to initiate intramolecular events that are ultimately responsible for signal transduction by AT receptors.

FOOTNOTES

*

This work was supported in part by Specialized Center of Research in Hypertension Grant HL33713 from the National Institutes of Health, a grant-in-aid from the American Heart Association/Northeast Ohio Affiliate Inc. (HANEO), and a HANEO fellowship (to K. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§

To whom correspondence should be addressed: Dept. of Molecular Cardiology, Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195. Tel.: 216-444-1269; Fax: 216-444-9263.

()

The abbreviations used are: Ang II or AII, the octapeptide hormone angiotensin II, NH-D-R-V-Y-I-H-P-F-COOH; L-162,163, [5,7-dimethyl-2-ethyl-3-[(4-[2(n-butyloxycarbonylsulfonamido)-isobutyl-thienyl]] phenyl]methylimidazol[4,5,6]pyridine (22); IP, inositol phosphate; HBSS, Hanks' balanced salt solution.

()

S. Sung and S. Karnik, unpublished observations.

ACKNOWLEDGEMENTS

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