Globular tertiary structures

We have seen that the forces that maintain the secondary structure of a protein are hydrogen bonds between the amide hydrogen and the carbonyl oxygen of the peptide bond. What are the forces that maintain the tertiary structure of a protein The globular tertiary structure forms spontaneously and is maintained as a result of interactions among the side chains, the R groups, of the amino acids. The structure is maintained by the following molecular interactions ... 

An example of globular tertiary structure of a protein is presented in Figure C5.14. This particular protein is called aspartic protease endothia-pepsin, but its name is not really important for us at the moment. Let s look first at the image C5.14 a. There, the spirals show the strands of a-spirals (there happens to be only a few of them in this particular protein), and the flat arrows represent the pieces which have /S-structure. This way of depicting the protein structure was suggested by the biophysicist Jane Richardson of Duke University. It is good for its clarity if you tried to draw tertiary structure in more detail, the picture would appear too... 

Cohen F E, M J E Sternberg and W R Taylor 1982 Analysis and Prediction of the Paclung oi. i-E a iinst a /3-Sheet in the Tertiary Structure of Globular Proteins. Journal of AdoljcuLir E 156 821-862. 

Equation (8.97) shows that the second virial coefficient is a measure of the excluded volume of the solute according to the model we have considered. From the assumption that solute molecules come into surface contact in defining the excluded volume, it is apparent that this concept is easier to apply to, say, compact protein molecules in which hydrogen bonding and disulfide bridges maintain the tertiary structure (see Sec. 1.4) than to random coils. We shall return to the latter presently, but for now let us consider the application of Eq. (8.97) to a globular protein. This is the objective of the following example. 

Figure 1.1 The amino acid sequence of a protein s polypeptide chain is called Its primary structure. Different regions of the sequence form local regular secondary structures, such as alpha (a) helices or beta (P) strands. The tertiary structure is formed by packing such structural elements into one or several compact globular units called domains. The final protein may contain several polypeptide chains arranged in a quaternary structure. By formation of such tertiary and quaternary structure amino acids far apart In the sequence are brought close together in three dimensions to form a functional region, an active site.

Several motifs usually combine to form compact globular structures, which are called domains. In this book we will use the term tertiary structure as a common term both for the way motifs are arranged into domain structures and for the way a single polypeptide chain folds into one or several domains. In all cases examined so far it has been found that if there is significant amino acid sequence homology in two domains in different proteins, these domains have similar tertiary structures. 

Cohen, F.E., Sternberg, M.J.E., Taylor, W.R, Analysis and prediction of the packing of a-helices against a p-sheet in the tertiary structure of globular proteins. 

Protein tertiar-y structure is also influenced by the environment. In water a globular- protein usually adopts a shape that places its hydrophobic groups toward the interior, with its polar- groups on the surface, where they are solvated by water molecules. About 65% of the mass of most cells is water, and the proteins present in cells are said to be in their native state—the tertiary structure in which they express their biological activity. When the tertiar-y structure of a protein is disrupted by adding substances that cause the protein chain to unfold, the protein becomes denatured and loses most, if not all, of its activity. Evidence that supports the view that the tertiary structure is dictated by the primary structure includes experiments in which proteins are denatured and allowed to stand, whereupon they are observed to spontaneously readopt then native-state conformation with full recovery of biological activity. 

When the polypeptide chains of protein molecules bend and fold in order to assume a more compact three-dimensional shape, a tertiary (3°) level of structure is generated (Figure 5.9). It is by virtue of their tertiary structure that proteins adopt a globular shape. A globular conformation gives the lowest surface-to-volume ratio, minimizing interaction of the protein with the surrounding environment. 

Because the tertiary structure of a globular protein is delicately held together by weak intramolecular attractions, a modest change in temperature or pH is often enough to disrupt that structure and cause the protein to become denatured. Denaturation occurs under such mild conditions that the primary structure remains intact but the tertiary structure unfolds from a specific globular shape to a randomly looped chain (Figure 26.7). 

Godzik, A., and Skolnick, J. (1992). Sequence-structure matching in globular proteins application to supersecondary and tertiary structure determination. Proc. Natl. Acad. Sci. U.S.A. 89, 12098-12102. 

The NMR spectrum given by a globular protein with a well-defined tertiary structure differs from that of the same protein under denaturing conditions in two respects. First, the reduction in mobility of residues when the protein folds into a stable tertiary structure produces a broadening of resonances. Second, alterations in resonances caused by chemical shifts arise due to the stable placement of specific protons in unique chemical environments which leads to the appearance of resonances in new positions. 

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