Synthetic site-directed ligands

Complexes of nucleotides, peptides and arom atic hapten-like compounds with immunoglobulin fragments were studied by X-ray analysis. Alter tri- or hexanucleotides of deoxythymidylate were diffused into triclinic crystals of a Fab (BV04- 01) with specificity for single-stranded DNA, extensive changes were detected throughout the structure of the protein. The Fab co-crystallized with a tri- or pentanucleotide in a different space group (monoclinic), an observation sometimes correlated with alterations in the structure of the ‘native’ protein. Structural analyses of the co-crystals are in progress for direct comparisons with the unliganded Fab. In crystals of a human (Meg) Bence-Jones dimer, synthetic opioid peptides, chemotactic peptides or dinitrophenyl (DNP) derivatives could be diffused into a large conical binding cavity. The conformations of both the ligand and the protein were usually altered during the binding process. At the base of the cavity tyrosine residues could be displaced like trap-doors to permit entry of some opioid peptides and DNP compounds into a deep binding pocket. In co-crystals of the dimer and bis(DNP)lysine, two ligand molecules were bound in tandem, one in the main cavity and the second in the deep pocket. One ligand adopted an extended conformation, with the ε-DNP ring near the floor of the main cavity and the α-DNP group in solvent outside the binding site. There were no significant conformational changes in the protein. In contrast, the second ligand was very compact, with both DNP rings immersed in the deep pocket, and the binding site was expanded to accommodate the oversized ligand. Peptides designed to be specific for the main cavity were incrementally constructed from minimal binding units by M. Geysen, G. Trippick, S. Rodda and their colleagues. A pentapeptide optimized for binding by this method was diffused into a crystal of the dimer and found by Fourier difference analysis to lodge exclusively in the main cavity as predicted. Binding regions in the BV04-01 Fab and the Meg dimer were markedly different in size and shape. The Fab had a groove-type site, in which a layer of sidechains acted like a false floor over regions analogous to the cavity and deep pocket of the Bence-Jones dimer.

Memoirs: The Development of the Skull of Scyllium (Scyliorhinus) canicula L

1. The development of the skull of Scyllium canicula has been studied from the first appearance of cartilage, through thirteen stages, up to the point at which the main features of the adult skull have been acquired. 2. The parachordals are the first elements to chondrify, and evidence is presented confirming Goodrich's observations concerning the visible traces of metameric segmentation of the metotic region of the paraohordal. 3. The auditory capsule chondrifies from the first in continuity with the parachordal, to which it is attached by the anterior basicapsular commissure. 4. The polar cartilages have not been found separate, but they appear as nodules of cartilage attached to the under surface of the anterior ends of the parachordals. 5. The orbital cartilage becomes attached to the parachordal by means of the pila antotica, and to the trabecula at the base of the lamina orbitonasalis by means of the preoptic root. 6. The hind wall of the pituitary fossa is formed in a complex manner, from a postpituitary commissure between the polar cartilages, and a pair of inwardly directed processes from the foremost ends of the parachordals forming the dorsum sellae. There is also a precarotid commissure, enclosing the carotid arteries in a foramen between itself and the postpituitary commissure. 7. The basicranial fenestra has been demonstrated. 8. Arguments are given for rejecting Allis's view that the so-called basicranial fenestrae throughout the craniates are not homologous. 9. Attention is called to the vacuity in the median wall of the auditory capsule through which the posterior canal bulges, and to the fact that this vacuity is not to be confused with the foramen endolymphaticum. 10. The relations of the glossopharyngeal nerve are described, and it is shown that its apparent passage through the cavity of the auditory capsule is to be ascribed to the fact that the lamina hypotica of the parachordal acts as a false floor to the auditory capsule, the true floor of which is in this region unchondrified. 11. The problem of the relations of the jaws to the brain-case is reviewed in the light of recent investigations, and a reasoned classification is attempted. 12. It is noticed that chondrification is delayed in embryonic material collected from Naples, as compared with material of similar size and degree of development obtained from Plymouth.