1.8 A structure of Hypoderma lineatum collagenase: a member of the serine proteinase family.

Collagenase from the fly larvae Hypoderma lineatum cleaves triple-helical collagen in a single region. It was crystallized at neutral pH in the absence of inhibitor and 1.8 A data were collected using synchrotron radiation and a Mark II prototype detector. The structure was solved by combining multiple isomorphous replacement methods and rotation translation function in real space. Refinement between 7 and 1.8 A using the program X-PLOR led to a final R factor of 16.9%. The overall fold is similar to that of other trypsin-like enzymes but the structure differs mainly by the presence of a beta-sheet at position 31-44. The two embedded molecules of the asymmetric unit are related by a pseudo twofold axis. The beta-sheet 31-44 of one molecule is involved in hydrogen bonds with binding-pocket residues of the other molecule. It thus completely prevents access to the active site. The specificity of this enzyme probably results from the position of Phe192 and Tyr99 at the entrance of the active site.

Small-molecule crystal structures as a structural basis for drug design.

For a long time, the crystal structures of small molecules were regarded as useful only for establishing the stereochemical formulae of the crystallized compounds. Recently, chemists have realized that in the study of the environment in the solid state there exists valuable structural information on the binding characteristics of chemical groups. Numerous comparisons have been made which show the nearly perfect correlation between small-molecule structural results, and the observed binding in receptor-substrate complexes. Moreover, the observed conformations of flexible substrates interacting with the neighbouring molecules in their crystal structures, can lead to valuable hypotheses on their conformation when bound in the active site of a biological macromolecule.

Configuration and preferential solid-state conformations of perindoprilat (S-9780). Comparison with the crystal structures of other ACE inhibitors and conclusions related to structure-activity relationships.

The conformation of perindoprilat, an antihypertensive drug, is studied in the solid state by X-ray analysis. The resolution of its structure reveals important analogies between its observed conformation and that of several ACE inhibitors of the same family. This comparison points out a constant relative orientation of the functional groups, regardless of the molecular environment. This angular constancy appears to us as not being accidental and is a good argument for the spatial design of the ACE binding site. Although ACE is a carboxydipeptidase, the binding site may not contain two but one unique hydrophobic pocket receiving the C-terminal end of the inhibitors.