Biomedical subjects
Publications and source records attributed to J A Jenkins.
X-ray studies of acid proteases indicate a bilobal structure with a well defined active site cleft. An intramolecular twofold symmetry axis relates two topologically similar domains and the active site residues. A possible mechanism for evolution by gene duplication, divergence and gene fusion is presented.
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A pancreatic polypeptide with some hormonal properties has been purified from chicken and turkey pancreas using acid-ethanol extraction, gel filtration and anion-exchange chromatography. The material has been crystallised. The crystals are monoclinic with space group C2. Preliminary isomorphous replacement experiments have so far provided a single-site derivative with Hg(NO3)2. A low-resolution electron density map phased with this derivative using anomalous scattering considered together with Patterson function calculations suggest that the molecules are partly helical and are arranged as a compact dimer about the crystallographic two-fold axis. The structure and association of these molecules are compared with those of insulin and glucagon, pancreatic protein and polypeptide hormones respectively, which have been studied in great detail.
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The molecular structures of two fungal acid proteases at 3 A resolution have been compared, and found to have similar secondary and tertiary folding. These enzymes are bilobal and have a pronounced cleft between the two lobes. This cleft has been identified as the active site region from inhibitor binding studies. The results of the comparison are discussed in terms of homology among the acid proteases in general.
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Thr relevance of the crystal structure of the polypeptide hormones, insulin, glucagon and human placental lactogen to conformation and flexibility in solution and to receptor binding is considered. X-ray studies for crystal forms of glucagon, human placental lactogen and three insulin derivatives (A1 acetyl insulin, A1-t-butoxy carbonyl insulin and A1 2,2-dimethyl-3-formyl-L-thiazolidine-4-carbonyl insulin) are reported. Neither glucagon nor human placental lactogen are as ordered as insulin in the crystal form. Glucagon crystals undergo distinct transformations on changing the pH of the mother liquor from pH 9.5 to pH 6, indicating that the glucagon molecule is flexible in the crystal, as it is in solution. On the other hand all insulin analogues have a similar three dimensional structure to that of native insulin. Three dimensional difference Fourier studies of two insulin derivatives at 3 A resolution indicate the position of the modifying groups and define the small conformational changes which have occurred. The in vitro biological activity and receptor binding decrease with the increasing size of the group added to A1. The correlation of the structure analysis with the biological data strongly implicate a region close to A1 in receptor binding. Insulin appears to bind to the receptor in a specific conformation similar to that observed in the crystal structure and in solution; amino acid residues which are separated in the primary structure but brought into close juxtaposition in the tertiary structure are important for full potency.
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