Editorial overview

Proteins Editorial overview Wire G.J. Hol University of Washington, Seattle, Washington, USA Current Opinion in Structural Biology 1992, 2:843-844 As everyone knows, proteins are composed of only 20 amino acids strung together as beads and folded into dynamic, often flexible and usually well defined structures. During the course of evolution, Nature has compensated for the limitation of a mere 20 building blocks by frequently m(xtifying amino acids, sometimes by incredibly complex pathways, by post-translational m(xtification processes. Balaram (pp845-851) describes in the first review m(xlern attempts to expand the existing repertoire by synthetic as well as molecular biological methods. It is clear that the 'non-coded' amino acids have a profound effect on conformational flexibility, and, obviously, on chemical reactivity. Balaram has provided a clear outline of the field, in which he considers peptide design as well as protein engineering. Personally, I never stop wondering why the 20 were chosen, and am very curious if the earth would have been better off with another set, or with an extended set of say 30 or 40 building blocks. In the latter case, the diversig' of life would almost certainly have been even greater than it is at the present time. Whether greater diversity wouk! have me-ant greater quality is, of course, impossible to say. The interplay of proteins and peptides is the subject of Marshall's review ( p p 9 0 4 919), which is impressively comprehensive, t te sketches the dramatic increase in understanding and observations in this field during the past few years, it turns out that nature is by no means dogmatic but, instead, flexible and adaptable. In certain cases, the protein hardly changes conformation ufxm peptide binding, but in other instances, significant and crucial conformational changes do occur. It will be a major challenge to computational protein specialists to find reasons for these differences in the adaptability of proteins, and, eventually, to be able to predict which changes in protein structure will occur. The field of protein-receptor interaction has received an enormous impetus by new discoveries, as de Vos and Kossiakoff (pp852-858) describe in their beautiful review. One recent result is the observation that the same receptor molecule can interact with a single hormone molecule in two different ways, but only in a distinct order. By doing so, dimerization of the receptor occurs, an event which seems at the heart of .several receptor-mediated processes. Much still needs to be elucidated but it is marvellous to see some of the most important mechanisms of cell-cell communication being unravelled at the three-dim(ensional and atomic levels.

Canters and van de Kamp (pp859--869), in a thorough and most educational review, show us a totally different aspect of protein molecules: their active participation in electron transfer processes. Indirect action involves positioning cofactors in incredibly precise manners as seen in the photosynthetic reaction centre. But in other cases, electrons flow through the protein matrix by processes which are not yet fully understo(xt, and which may be very diverse even in a single electron transfer complex. Numerous studies, theoretical as well as experimental, are underway to further our understanding in this importam area, where molecular biology and quantum chemistry meet c~ach other. Muirhead and Watson (pp870-876) do not follow the path of a single elementary particle flowing from protein to protein, but foUow metabolites being handed down from en'zyme to enz3'me in a single metatx.~lic pathway. Glycolysis is the first major pathw~ly for which all enzymes have now been characterized in three dimensions. It is interesting, and intriguing, that all of them are based on a/[~ proteins of two distinct and unrelated classes: the 'Rossmann fold" type and the '[B/a barrel' type. In contrast with other pathways, e.g. the tryptophan synthase pathway, we see no evidence for a common ancestral protein. The only common theme appears to be that the active sites are located at the carboxTl terminus of the ]3-sheet. This seems to be a very weak case for common ancestry of all members of the pathway, even though, obviously, the product of one enz3,rne is the substrate of the next enzTme in the pathway. Glycolysis yields pyruvate which, in man}, organisms, is processed further in a fascinating multi-enzyme complex, described masterfully by Mattevi, de Kok and Perham ( p p 877-887). The past year has seen tremendous progress in the structural elucidation, both by crystallography and NMR, of the pyruvate dehydrogenase complex, one of the most sophisticated molecules develot'x."d during the course of evolution. The key role is played by the lipoyl group of the lipoyl domain of the E2 subunit, which is swirling around and visiting three different active centres. The catalytic domain of the same E2 subunit forms trimers which assemble into large hollow truncated cubes or icosahedrons. The large E1 and E3 en'zymes are draped around this hollow framework in a manner which is still the subject of lively debate. We see here a nice example of, on the one hand, the sturdiness of proteins, as reflected in the core of the complexes,

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Proteins

and, on the other hand, the flexibility of proteins, as seen in the highly mobile lipoyl domain. Thornton (pp888-894) brings us back to a more general level by analyzing protein structures reported so far. The number of structures reported is growing very rapidly at present, although many of the new entries of the Br(x}khaven Protein Data Bank are site-directed mutants or obvious members of protein families whose structures are alrc-ady known. The analysis of protein structures has recently led to interesting and quite powerful tools for the detection of errors in protein structures. This is a major contribution to the field which is also of relevance for assessing the quality of three-dimensional models of proteins derived by theoretical approaches. Another very active field described by Thornton is the development of tools to discover, from primary structure, structural relationships among proteins with very little sequence homologT. In their wide-ranging rm4ew, Murzin and Chothia (pp895-903) describe a remarkable fact: not less than ten new protein families have been reported over the past few years, and yet, despite this impressive advance of our knowledge, there is the suggestion that there exist no more than ~ 1000 definitive protein topologies. This gives the field a certain horizon, a cem~in fin-de-siecle

feeling. We should not, however, be deceived by such a statement. After all, only -,-10% of the tx~ssible folds have been descrilx~ct, if the prediction is correct. Moreover, it is still hard to see, for example, how the topology of the choleratoxin and verotoxin B subunits can be derived from knowing that of staphylococcal nuclc~ase. Mso, the architecture of multisubunit proteins is surprisingly variable and dependent on small effects, as sickle cell hemoglobin illustrates so dramatically. Life depends on exquisite line tuning for function, shape and motion, and this is also true at the level of protein molecules. It is clear that the discoveries being made at present at the atomic and three-dimensional level of proteins will, in due course, have a major impact on the quality of life. The reviews of receptor and peptide binding show that three-dimensional structures of proteins form a marvellous starting point for molecular medicine, and should allow interdisciplinary teams of 'molecular doctors' to design many useful drugs as well as vaccines and smart proteins targetted ve~" precisely at specific cell types.

WGJ 11ol, Department of Biological Structure, H~.~lth ~'iences Building, SM 20, Sc|ux~l c~f M~ticine, University of Washington, Seattle, Washing. ton 98195, USA.