Biomedical subjects

Terry Kenakin

Publications and source records attributed to Terry Kenakin.

22 records · Page 2Linked to original sources

PubMed2002

G protein-coupled receptor allosterism and complexing.

G protein-coupled receptors (GPCRs) represent the largest family of cell-surface receptors. These receptors are natural allosteric proteins because agonist-mediated signaling by GPCRs requires a conformational change in the receptor protein transmitted between two topographically distinct binding sites, one for the agonist and another for the G protein. It is now becoming increasingly recognized, however, that the agonist-bound GPCR can also form ternary complexes with other ligands or "accessory" proteins and display altered binding and/or signaling properties in relation to the binary agonist-receptor complex. Allosteric sites on GPCRs represent novel drug targets because allosteric modulators possess a number of theoretical advantages over classic orthosteric ligands, such as a ceiling level to the allosteric effect and a potential for greater GPCR subtype-selectivity. Because of the noncompetitive nature of allosteric phenomena, the detection and quantification of such effects often relies on a combination of equilibrium binding, nonequilibrium kinetic, and functional signaling assays. This review discusses the development and properties of allosteric receptor models for GPCRs and the detection and quantification of allosteric effects. Moreover, we provide an overview of the current knowledge regarding the location of possible allosteric sites on GPCRs and candidate endogenous allosteric modulators. Finally, we discuss the potential for allosteric effects arising from the formation of GPCR oligomers or GPCRs complexed with accessory cellular proteins. It is proposed that the study of allosteric phenomena will become of progressively greater import to the drug discovery process due to the advent of newer and more sensitive GPCR screening technologies.

Allosteric Regulation↗

PubMed2002

Drug efficacy at G protein-coupled receptors.

Efficacy has been defined in receptor pharmacology as a proportionality factor denoting the amount of physiological response a given ligand imparts to a biological system for a given amount of receptor occupancy. While first defined in terms of response, the concept can be expanded to a wide variety of G protein-coupled receptor (GPCR) behaviors, which includes pleiotropic interaction with multiple G proteins, internalization, oligomerization, desensitization, and interaction with membrane auxilliary proteins. Thus, there can be numerous types of efficacy, and different ligands can have a range of efficacies for different receptor behaviors. This review discusses the use of the efficacy concept in GPCR models based on the thermodynamic linkage theory and also in terms of the protein ensemble theory, in which macroaffinity of ligands for an ensemble of receptor microstates produces a new ligand-bound ensemble. The pharmacological characteristics of the ligand emerge from the intersection of the ligand-bound ensemble with the various ensembles defining pharmacological receptor behaviors. Receptor behaviors discussed are activation of G proteins; ability to be phosphorylated, desensitized, and internalized; formation of dimers and oligomers; and the interaction with auxiliary membrane and cytosolic proteins. The concepts of ligand-specific receptor conformation and conditional efficacy are also discussed in the context of ligand control of physiological response.

Animals↗

PubMed2002

CCR5 chemokine receptors: gatekeepers of HIV-1 infection.

With the discovery that CCR5 is the critical protein required for infection by M-tropic HIV, has come huge research efforts, both in academia and industry, to try to exploit this finding. Thus, research advances in the fields of virology, structural protein chemistry, and receptor pharmacology have combined to add a new understanding to the process of HIV fusion and possible mechanisms to prevent HIV entry. This review will approach this field from a receptor pharmacology viewpoint and outline some concepts of receptor allosterism and protein-protein interaction which may be relevant to CCR5 blockade. Many of these ideas may be explored in a practical sense with the advent of new small molecule CCR5 inhibitors currently entering the clinic.

Acquired Immunodeficiency Syndrome↗

PubMed2002

GPCR drug discovery through the exploitation of allosteric drug binding sites.

G-protein-coupled receptors (GPCRs) represent the most important class of drug targets both in terms of therapeutic benefit and pharmaceutical sales. The majority of current GPCR drugs have been identified in ligand binding assays and interact with the receptor in a competitive manner with the natural ligand. There is increasing evidence that it is possible to identify GPCR agonist and antagonist ligands that do not interact at the natural ligand binding site, rather such compounds interact elsewhere on the receptor to modulate receptor activity. This finding allows the possibility that there may be many as yet uncharacterized drug binding sites within the GPCR that could be exploited for therapeutic intervention. The characterization of such "allosteric" ligand interaction sites, following the identification of molecules capable of interacting at these sites, would be expected to lead to the identification of drug molecules with improved selectivity and efficacy. Such activities may enable the identification of selective ligands at GPCRs for which competitive natural ligand binding screens have been unsuccessful. In this manuscript we review known examples of GPCR allosteric ligands, the functional assay technologies that are being employed to identify further ligands of this type, and the potential benefit that may result from the identification of such ligands.

Allosteric Site↗