A qualitative model for the histamine H3 receptor explaining agonistic and antagonistic activity simultaneously.

A pharmacophore model for histamine H3 ligands is derived that reveals the putative interaction of both H3 agonists and antagonists with an aspartate residue of the receptor. This interaction is determined by applying the density functional theory implemented in a program package adapted for parallel computers. The model reveals a molecular determinant explaining efficacy as the conformation of the aspartic acid residue differs according to whether it is binding to agonists or antagonists.

The ligand-receptor-G-protein ternary complex as a GTP-synthase. steady-state proton pumping and dose-response relationships for beta -adrenoceptors.

Steady-state solutions are developed for the rate of G alpha.GTP production in a synthase model of the ligand-receptor-G-protein ternary complex activated by a ligand-receptor proton pumping mechanism. The effective rate, k(31), defining the proton transfer, phosphorylation and G alpha.

Characterization of the binding site of the histamine H(3) receptor. 2. Synthesis, in vitro pharmacology, and QSAR of a series of monosubstituted benzyl analogues of thioperamide.

A series of monosubstituted benzyl analogues of the histamine H(3) receptor antagonist thioperamide were synthesized and evaluated for their histamine H(3) receptor activity on the guinea pig jejunum. Incorporation of Cl, Br, and I at the ortho position of the benzyl moiety led to an increase of the pA(2) value, whereas the same substituents at the para position led to a decrease. However, a fluorine substituent gave a strong decrease in pA(2), regardless of the position.

Trimeric G alpha beta gamma protein coupling to a 3D model of G protein-coupled receptors confirming a new molecular mechanism for activation.

The present-day model for G protein activation and the associated theory on how a G protein-coupled receptor may activate the G protein are summarized. Experimental data are outlined which seem not to be in accordance with this present-day model. An alternative molecular mechanism for ternary complex activation is presented together with a three-dimensional model for a receptor coupled to the appropriate trimeric G protein.

Development of a three-dimensional CysLT1 (LTD4) antagonist model with an incorporated amino acid residue from the receptor.

This paper describes the molecular modeling of leukotriene CysLT1 (or LTD4) receptor antagonists. Several different structural classes of CysLT1 antagonists were superimposed onto the new and highly rigid CysLT1 antagonist 8-carboxy-3'-[2-(2-quinolinyl)ethenyl]flavone (1, VUF 5017) to generate a common pharmacophoric arrangement. On the basis of known structure-activity relationships of CysLT1 antagonists, the quinoline nitrogen (or a bioisosteric equivalent thereof) and an acidic function were taken as the matching points.

The agonistic binding site at the histamine H2 receptor. II. Theoretical investigations of histamine binding to receptor models of the seven alpha-helical transmembrane domain.

In the first part (pp. 461-478 in this issue) of this study regarding the histamine H2 receptor agonistic binding site, the best possible interactions of histamine with an alpha-helical oligopeptide, mimicking a part of the fifth transmembrane alpha-helical domain (TM5) of the histamine H2 receptor, were considered. It was established that histamine can only bind via two H-bonds with a pure alpha-helical TM5, when the binding site consists of Tyr182/Asp186 and not of the Asp186/Thr190 couple.

The agonistic binding site at the histamine H2 receptor. I. Theoretical investigations of histamine binding to an oligopeptide mimicking a part of the fifth transmembrane alpha-helix.

Mutation studies on the histamine H2 receptor were reported by Gantz et al. [J. Biol.

GTP synthases. Proton pumping and phosphorylation in ligand-receptor-G alpha-protein complexes.

A structural model for a ligand-receptor-Gs alpha-protein complex to function as a GTP synthase is presented. The mechanism which is dependent on the movement and rotation of the G alpha-protein alpha 2-helix is seen to involve the delivery of, at least, one proton to the phosphorylation site in the rotation of this helix. The cycle is driven by a ligand-mediated proton pump through the alpha-helices of the receptor, attachment of the conserved Tyr-Arg-Tyr receptor proton shuttle being made to an aspartate group on the Gs alpha-protein terminal sidechain, which is itself linked to the Asn-Gln interaction known to control movement and rotation of the alpha 2-helix between .

Modelling and mutation studies on the histamine H1-receptor agonist binding site reveal different binding modes for H1-agonists: Asp116 (TM3) has a constitutive role in receptor stimulation.

A modelling study has been carried out, investigating the binding of histamine (Hist), 2-methylhistamine (2-MeHist) and 2-phenylhistamine (2-PhHist) at two postulated agonistic binding sites on transmembrane domain 5 (TM5) of the histamine H1-receptor. For this purpose a conformational analysis study was performed on three particular residues of TM5, i.e.

Does the ternary complex act as a secondary proton pump and a GTP synthase?

It has been suggested that G protein-coupled receptors can act as proton transporters, with the activated G protein-coupled receptor transporting H+ across the membrane from the extracellular side to the cytoplasm. In this article, Paul Nederkoorn, Henk Timmerman and Gabriëlle Donné-Op den Kelder summarize the various H+ translocation mechanisms and how these compare with activated G protein-coupled receptors. The G protein, being part of the ternary complex, is proposed to use translocated protons to synthesize GTP from GDP and Pi, thus functioning in a similar manner to ATP synthase.

A new model for the agonistic binding site on the histamine H2-receptor: the catalytic triad in serine proteases as a model for the binding site of histamine H2-receptor agonists.

The historical model for the agonistic binding site on the histamine H2-receptor is based on a postulated activation mechanism: it has been suggested that the histamine monocation binds to the histamine H2-receptor via the formation of three hydrogen bonds. The cationic ammonium group in the side chain and the -NH- group in the tau-position of the imidazole act as proton donors, whereas the =N- atom in the pi-position of the imidazole acts as a proton acceptor. Participation of the ammonium group in H-bonding with a presumed negative charge on the receptor leads to a decrease in positive charge, which is thought to induce a tautomeric change in the imidazole ring system from N tau-H to N pi-H.