Alan H. Katz

Two N-terminal domains of Kv4 K(+) channels regulate binding to and modulation by KChIP1.

The family of calcium binding proteins called KChIPs associates with Kv4 family K(+) channels and modulates their biophysical properties. Here, using mutagenesis and X-ray crystallography, we explore the interaction between Kv4 subunits and KChIP1. Two regions in the Kv4.2 N terminus, residues 7-11 and 71-90, are necessary for KChIP1 modulation and interaction with Kv4.2. When inserted into the Kv1.2 N terminus, residues 71-90 of Kv4.2 are also sufficient to confer association with KChIP1. To provide a structural framework for these data, we solved the crystal structures of Kv4.3N and KChIP1 individually. Taken together with the mutagenesis data, the individual structures suggest that that the Kv4 N terminus is required for stable association with KChIP1, perhaps through a hydrophobic surface interaction, and that residues 71-90 in Kv4 subunits form a contact loop that mediates the specific association of KChIPs with Kv4 subunits.

Thallium in organic synthesis. 68. A convenient synthesis of 2-phenylindoles from anilides

Abstract Thallation of anilides with TTFA in a mixture of TFA and ether gives ortho-thallated derivatives, which yield 2-acetamido-tolanes upon reaction with copper(I) phenylacetylide in acetonitrile. Treatment of the latter compounds with palladium(II) chloride results in ring closure to give 1-acyl-2-phenylindoles, from which 2-phenyl-indoles are obtained by alkaline hydrolysis.

Modeling G protein-coupled receptors for structure-based drug discovery using low-frequency normal modes for refinement of homology models: Application to H3 antagonists

G Protein‐Coupled Receptors (GPCRs) are integral membrane proteins that play important role in regulating key physiological functions, and are targets of about 50% of all recently launched drugs. High‐resolution experimental structures are available only for very few GPCRs. As a result, structure‐based drug design efforts for GPCRs continue to rely on in silico modeling, which is considered to be an extremely difficult task especially for these receptors. Here, we describe Gmodel, a novel approach for building 3D atomic models of GPCRs using a normal mode‐based refinement of homology models. Gmodel uses a small set of relevant low‐frequency vibrational modes derived from Random Elastic Network model to efficiently sample the large‐scale receptor conformation changes and generate an ensemble of alternative models. These are used to assemble receptor–ligand complexes by docking a known active into each of the alternative models. Each of these is next filtered using restraints derived from known mutation and binding affinity data and is refined in the presence of the active ligand. In this study, Gmodel was applied to generate models of the antagonist form of histamine 3 (H3) receptor. The validity of this novel modeling approach is demonstrated by performing virtual screening (using the refined models) that consistently produces highly enriched hit lists. The models are further validated by analyzing the available SAR related to classical H3 antagonists, and are found to be in good agreement with the available experimental data, thus providing novel insights into the receptor–ligand interactions. Proteins 2010.

Thallium in organic synthesis. 63. A convenient synthesis of aromatic nitriles

Abstract Aromatic nitriles are readily formed by heating arylthallium bis(trifluoroacetates) with CuCN in acetonitrile.

Thallium in organic synthesis: XLIV. Electrophilic thallation of electron-rich arenes☆

Abstract Electron-rich arenes, which normally undergo oxidative coupling to biaryls with TTFA/TFA, can be smoothly thallated in high yield with TTFA in a 1/1 mixture of TTFA and ether.