Retinal orientation and interactions in rhodopsin reveal a two-stage trigger mechanism for activation

The 11-cis retinal chromophore is tightly packed within the interior of the visual receptor rhodopsin and isomerizes to the all-trans configuration following absorption of light. The mechanism by which this isomerization event drives the outward rotation of transmembrane helix H6, a hallmark of activated G protein-coupled receptors, is not well established. To address this question, we use solid-state NMR and FTIR spectroscopy to define the orientation and interactions of the retinal chromophore in the active metarhodopsin II intermediate. Here we show that isomerization of the 11-cis retinal chromophore generates strong steric interactions between its β-ionone ring and transmembrane helices H5 and H6, while deprotonation of its protonated Schiff’s base triggers the rearrangement of the hydrogen-bonding network involving residues on H6 and within the second extracellular loop. We integrate these observations with previous structural and functional studies to propose a two-stage mechanism for rhodopsin activation

Helix movement is coupled to displacement of the second extracellular loop in rhodopsin activation

The second extracellular loop (EL2) of rhodopsin forms a cap over the binding site of its photoreactive 11-cis retinylidene chromophore. A crucial question has been whether EL2 forms a reversible gate that opens upon activation or acts as a rigid barrier. Distance measurements using solid-state 13C NMR spectroscopy between the retinal chromophore and the β4 strand of EL2 show that the loop is displaced from the retinal binding site upon activation, and there is a rearrangement in the hydrogen-bonding networks connecting EL2 with the extracellular ends of transmembrane helices H4, H5 and H6. NMR measurements further reveal that structural changes in EL2 are coupled to the motion of helix H5 and breaking of the ionic lock that regulates activation. These results provide a comprehensive view of how retinal isomerization triggers helix motion and activation in this prototypical G protein-coupled receptor. © 2009 Nature America, Inc. All rights reserved

Towards a Mathematical Foundation for Design Patterns

We identify a compact and sufficient set of building blocks which constitute most design patterns of the GoF catalog: uniform sets of classes or functions, function clans, class hierarchies, and regularities (morphisms) thereof. The abstractions observed are manifested within a model in symbolic logic and defined in LePUS, a declarative, higher order language. LePUS formulae concisely prescribe design patterns in a general, complete, and accurate manner. We provide a natural, condensed graphic notation for every LePUS formula and demonstrate how design patterns are faithfully portrayed by diagrams in this notation. We conclude by defining refinement (specialization) between patterns by means of predicate calculus and illustrate how the logical formalism of LePUS facilitates tool support for the recognition and implementation of design patterns

Towards a Mathematical Foundation for Design Patterns

We identify a compact and sufficient set of building blocks which constitute most design patterns of the GoF catalog: uniform sets of classes or functions, function clans, class hierarchies, and regularities (morphisms) thereof. The abstractions observed are manifested within a model in symbolic logic and defined in LePUS, a declarative, higher order language. LePUS formulae concisely prescribe design patterns in a general, complete, and accurate manner. We provide a natural, condensed graphic notation for every LePUS formula and demonstrate how design patterns are faithfully portrayed by diagrams in this notation. We conclude by defining refinement (specialization) between patterns by means of predicate calculus and illustrate how the logical formalism of LePUS facilitates tool support for the recognition and implementation of design patterns

LePUS - A Declarative Pattern Specification Language

At present, the only means used for specifying design patterns are contemporary object notations [Rumbaugh et. al 91; Booch 94], lengthy verbal descriptions, and sample programs. The inherent ambiguity and incompleteness of these means preclude devising tool support and fuel disputes over "their true intention". We identified a compact set of abstractions with simple graphical representation, which translates to precise, higher-order logic language. The visual language we present was construed to straightforwardly reflect regularities in design patterns and in O-O software in general. Several illuminating examples are analyzed to demonstrate the use of this language. Keywords: Design patterns, category theory, formal methods, software architecture 1. Introduction Despite vast interest in design patterns [GoF 95; Coplien & Schmidt 95; Vlissides, Coplien & Kerth 96; Buschmann et. al 96; Pree 94], and in the "pattern" form as means of conveying expertise in software design, little had be..

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