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Three-dimensional structures of Dendrotoxin (DtX), Toxin-I (DpI), and Toxin-K (DpK) were determined using molecular mechanics and molecular dynamics techniques. The overall molecular conformation and protein folding of the three dendrotoxins are very similar to the published crystal structures of bovine pancreatic trypsin inhibitor (BPTI) and alpha-DtX. Major secondary structural regions of the dendrotoxins are stable without much fluctuation during the dynamics simulation; the regions corresponding to the turns and bends (rich in lysines and arginines) exhibit more fluctuations. The conformational angles and the C alpha...C alpha' distances of the three disulfides (in each of the dendrotoxins) are different from each other. Comparative model building studies, involving the dendrotoxins and the proteinases, reveal that the key interactions (observed in BPTI-trypsin complex) needed for anti-protease activity are absent due to structural differences between the dendrotoxins and BPTI at the anti-protease loop; this explains the inability of the dendrotoxins to inhibit proteinases. The model also suggests that the solvent-exposed beta-turn region, rich in lysines (residues 26-28), might bind directly to the extracellular anionic sites of the receptors (K+ channels) by ionic interactions. The strikingly homologous cysteine distribution (Cys-x-x-x-Cys) in DtX, DpI, and DpK, at the C-terminus, induces the occurrence of a characteristic conformational motif, consisting of an alpha-helix (in an amphiphilic environment) stabilized by two disulfides, one involving a cysteine at the beta-strand, and the other at the N-terminus. This amphiphilic secondary structural element seems to provide the rigid frame work needed for exposing the proposed active site region of the dendrotoxins to the anionic sites of the K+ channel receptors.

The active (+) enantiomer of the antiinflammatory agent etodolac (1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]-indole-1-acetic acid) has been assigned an S absolute configuration on the basis of a crystallographic analysis of the (S)-(-)-borneol ester of (-)-etodolac, and the conformation of etodolac has been determined by a crystallographic analysis of (+/-)-etodolac. Analyses of the solid-state conformation, as well as energy-minimized conformations obtained by molecular mechanics calculations, have failed to provide a basis for identifying a probable receptor-site conformation.

IntroductionPotassium adenosine diphosphate dihydrate, K +.C10 HNNSOIOP~-. 2H20 , crystallizes in the orthorhombic space group P2~2~2 with four molecules in a unit cell of dimensions a --28.491 (6), b --10.446 (3) and c = 6.316 (1) A. The structure was solved by direct methods and refined to an R index of 0.062 (R w = 0.076) on 1384 intensities. The mean e.s.d.'s in bond lengths and angles are 0.013 A and 0.7 ° respectively. The crystal structure has revealed that the adenosine diphosphate exists as a zwitterion with N(1) of the base protonated and the pyrophosphate group dinegatively charged (one negative charge on each phosphate) and has provided details of the molecular conformation and chirality of the chelate ring. The two water molecules in the asymmetric unit are distributed over three positions, two on the same diad axis and one in a general position. The molecule is folded into one of the preferred compact conformations, viz. sugar pucker 2E (P---163.3 °, r m = 38.3°), the exocyclic C(4')-C(5') bond torsion angle ~ gauche + (57.8 °) and the glycosyl torsion angle X anti (32.4°), with an anionic oxygen of the o-phosphate and the hydroxyl oxygen of the fl-phosphate ligated to the K + ion. A second anionic oxygen of the fl-phosphate forms a slightly weaker coordination to the metal; thus, the metal ion is engaged in an tt,fl, fl chelate complex. In addition, the metal ion is coordinated to the base N(3), the ribose 0(2'), the anionic phosphate oxygen O(13) of neighboring nucleotides, and to one of the water molecules on the diad axis. Thus, the K + ion is surrounded by seven possible ligands. The chirality of the chelate ring corresponds to the A diastereomer. The N(1) and N(6) sites and N(6) and N(7) sites of the adenine base form pairs of hydrogen bonds with the oxygens of the ~-phosphate groups of neighboring molecules. There are no basestacking interactions observed in the structure.