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Bidirectional, iterative approach to the structural delineation of the functional "chemoprint" in GPR40 for agonist recognition.

ABSTRACT: GPR40, free fatty acid receptor 1 (FFAR1), is a member of the GPCR superfamily and a possible target for the treatment of type 2 diabetes. In this work, we conducted a bidirectional iterative investigation, including computational modeling and site-directed mutagenesis, aimed at delineating amino acid residues forming the functional "chemoprint" of GPR40 for agonist recognition. The computational and experimental studies revolved around the recognition of the potent synthetic agonist GW9508. Our experimentally supported model suggested that H137(4.56), R183(5.39), N244(6.55), and R258(7.35) are directly involved in interactions with the ligand. We have proposed a polarized NH-pi interaction between H137(4.56) and GW9508 as one of the contributing forces leading to the high potency of GW9508. The modeling approach presented in this work provides a general strategy for the exploration of receptor-ligand interactions in G-protein coupled receptors beginning prior to acquisition of experimental data.

SUBMITTER: Tikhonova IG

PROVIDER: S-EPMC3592210 | biostudies-literature | 2007 Jun

REPOSITORIES: biostudies-literature

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Bidirectional, iterative approach to the structural delineation of the functional "chemoprint" in GPR40 for agonist recognition.

Tikhonova Irina G IG Sum Chi Shing CS Neumann Susanne S Thomas Craig J CJ Raaka Bruce M BM Costanzi Stefano S Gershengorn Marvin C MC

Journal of medicinal chemistry 20070607 13

GPR40, free fatty acid receptor 1 (FFAR1), is a member of the GPCR superfamily and a possible target for the treatment of type 2 diabetes. In this work, we conducted a bidirectional iterative investigation, including computational modeling and site-directed mutagenesis, aimed at delineating amino acid residues forming the functional "chemoprint" of GPR40 for agonist recognition. The computational and experimental studies revolved around the recognition of the potent synthetic agonist GW9508. Our ...[more]

PMID: 17552505

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Project description:The present study aims at delineating violence from aggression, using genetically selected high (SAL, TA, NC900) and low (LAL, TNA NC100) aggressive mouse strains. Unlike aggression, violence lacks intrinsic control, environmental constraints as well as functional endpoints. Conventional measures namely latency, frequency and duration were used initially to accomplish the objective of delineation using the above strains. However, these quantitative measures fail to reveal further details beyond the magnitude of differential aggression, especially within the high aggressive mouse strains. Hence, it was necessary to analyze further, the behavioral sequences that make up the agonistic encounter. Novel measures such as threat/(attack + chase) (T/AC) and offense/withdrawal (O/W) ratios, context dependency and first-order Markov chain analysis were used for the above purpose. Our present analyses reveal clear qualitative behavioral differences between the three high aggressive selection strains based on the following facets namely structure and context in an agonistic interaction. Structure refers to a detailed study of the agonistic interaction components (ritualistic display, offense and sensitivity to the opponent submission cues) between any two subjects (inter-male interaction for the present study). Context refers to the capacity to identify an opponent by nature of its state (free moving/anesthetized), sex and the environment (home/neutral territory). NC900 displayed context dependency and structurally a rich repertoire of agonistic interaction components with an opponent. SAL failed to show discrimination and its inter-male agonistic behavior is restricted to a repetitive and an opponent-insensitive pattern of attack and chase. TA was comparable to SAL in terms of the structure but sensitive to context variables. Thus, SAL seems to display a violent form of aggressive behavior, while NC900 display 'functional' hyperaggression against a docile opponent in an inter-male agonistic interaction.

Dataset Information

Bidirectional, iterative approach to the structural delineation of the functional "chemoprint" in GPR40 for agonist recognition.

Publications

Bidirectional, iterative approach to the structural delineation of the functional "chemoprint" in GPR40 for agonist recognition.

Similar Datasets

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