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Biomedical subjects

C C Blake

Publications and source records attributed to C C Blake.

At least 55 records · Page 3Linked to original sources
PubMed1981

Phosphoglycerate kinase.

Phosphoglycerate kinase catalyses the high-energy phosphoryl transfer of the acyl phosphate of 1,3-bisphosphoglycerate to ADP to produce ATP, a reaction requiring magnesium ions. The enzyme is widely distributed and apparently highly conserved as a monomer of molecular mass 45 000. X-ray studies of the enzymes from horse muscle and yeast, carried out in Oxford and Bristol respectively, have shown that the molecular structures of the two enzymes are almost identical. The most striking aspect of the structure is that the single polypeptide chain is organized into two separated domains composed of the N-terminal and C-terminal halves of the chain. Substrate binding studies and the determination of the complete amino acid sequence of the horse enzyme suggest that the nucleotide substrates and the phosphoglycerate substrates are bound to the C-domain and N-domain, respectively, in sites that are separated by about 12 A. In order to bring the two substrates together for catalysis, a hinge-bending conformational change involving helix rotation has been proposed, for which there is independent evidence from solution studies. Crystals of the ternary complex of the horse enzyme have been prepared that may contain the folded form of the enzyme.

Amino Acid Sequence↗
PubMed1981

Prealbumin and the thyroid hormone nuclear receptor.

The thyroid hormones exhibit a wide range of biological activities, which are now thought to be mediated by a specific receptor molecule in the nucleus of the target cells. This receptor appears to promote the production of new mRNA molecules, leading to the synthesis of proteins, but the precise mode of action of the receptor and the nature of the gene products are not known at present. Thyroid hormone binding proteins are also present in the blood plasma; in humans there are two distinct binding proteins, thyroxine binding globulin (TBG) and prealbumin (PA), sometimes known as thyroxine binding (TBPA). In addition to its hormone binding function PA is also involved in vitamin A transport through a protein-protein interaction with the specific vitamin A binding protein in plasma, retinol-binding protein (RBP). Prealbumin has been subjected to an extensive X-ray analysis of its molecular structure and interactions with the thyroid hormones. The PA molecule is a tetramer of 55 000 relative molecular mass, composed of identical subunits. The structure of the subunit is essentially an eight-stranded beta-barrel. The subunits are organized in the tetramer by extensive hydrogen-bond and hydrophobic contacts, giving rise to a prealbumin molecule with a channel running right through its centre, and two deep cylindrical-helical depressions in its outer surface. The central channel contains two identical binding sites for the thyroid hormones, which closely match the shape and chemistry of the iodothyronine nucleus of the hormones. The two deep surface depressions have found to be structurally complementary to the DNA double helix. This structural information on prealbumin may be appropriate to the nuclear receptor in the light of recent studies that suggest a considerable degree of functional similarity between the two molecules. In particular, the receptor appears to be composed of two units: a thyroid hormone binding unit, or core receptor, and a regulatory unit that modulates the hormone binding; this latter protein may be a histone. Separating the hormone binding unit from the holoreceptor radically changes the binding affinity for the thyroid hormones and their analogues, with the pattern of binding in the core receptor showing a striking similarity to the pattern in prealbumin. These and other similarities between the two proteins are examined, and possible relationships are considered.

Animals↗
PubMed1980

The crystal structure of tortoise egg-white lysozyme at 6 A resolution.

Lysozyme extracted from the egg-white of tortoise, the first example of a reptilian lysozyme to have been purified, has been crystallized and its tertiary structure determined at low resolution by X-ray analysis. This structure is shown to be closely homologous to that of hen egg-white lysozyme. The crystals of tortoise egg-white lysozyme contain a large proportion of liquid and the X-ray map shows that this forms large channels through the crystals into which the active sites of the enzyme molecules open. This indicates that tortois lysozyme crystals may be suitable for low-temperature studies of true enzyme substrate complexes.

Animals↗
PubMed1979

Crystallographic studies of the dynamic properties of lysozyme.

The patterns of atomic displacements in the crystals of hen and human lysozyme derived from independent crystallographic refinement are broadly similar. Analysis of the pattern indicates a close correlation with molecular structure, strongly suggestive of intramolecular motion. The active site of lysozyme is located in a region of high displacement. It is concluded that protein mobility may play a significant part in biological activity and that X-ray crystallography can contribute to its analysis.

Animals↗
PubMed1979

Sequence, structure and activity of phosphoglycerate kinase: a possible hinge-bending enzyme.

The fitting of sequenced peptides to a high-resolution X-ray map of phosphoglycerate kinase has yielded the complete sequence and structure of the horse muscle enzyme. Metal ADP and ATP substrates are bound to one of the two widely separated domains in an environment that seems unsuitable for phosphoglycerate binding. The most plausible binding site for the phosphoglycerate substrate is on the other domain about 10 A from the ATP, which implies the possibility of a large scale hinge-bending of the domains to bring the two substrates together in a water-free environment for catalysis.

Amino Acid Sequence↗
PubMed1978

Hormone receptors.

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Receptors, Cell Surface↗
PubMed1977

Protein-DNA and protein-hormone interactions in prealbumin: a model of the thyroid hormone nuclear receptor?

High resolution X-ray analysis of the hormone-binding protein prealbumin has shown that it has a structural complementarity to double-helical DNA. The proposed binding site is composed of two symmetry-related beta-sheets containing a pair of helically disposed arms, which can interact with the bases in the wide groove of DNA. A palindromic target sequence is indicated by the symmetry of the protein. The two identical thyroid hormone binding sites on prealbumin are located in a channel that runs completely through the molecule. These two structural features suggest prealbumin as a model for the thyroid hormone nuclear receptor, providing a number of detailed predictions of its properties.

Amino Acid Sequence↗