Three-dimensional structure of protein

Kajava, A.V., Vassart, G., Wodak, S.J. Modelling of the three-dimensional structure of proteins with the typical leucine-rich repeats. Structure 3 867-877, 1995. 

The three-dimensional structure of protein molecules can be experimentally determined by two different methods, x-ray crystallography and NMR. The interaction of x-rays with electrons in molecules arranged in a crystal is used to obtain an electron-density map of the molecule, which can be interpreted in terms of an atomic model. Recent technical advances, such as powerful computers including graphics work stations, electronic area detectors, and... 

Clore, G.M., Gronenborn, A.M. Determination of three-dimensional structures of proteins and nucleic acids in solution by nuclear magetic resonance spectroscopy. CRC Crit. Rev. Biochem. 24 479-564, 1989. 

Greer J, Erickson JW, Baldwin, JJ, Varney MO. Application of three-dimensional structures of protein target molecules in structure-based drug design. J Med Chem 1994 37 1035-54. 

One Holy Grail in protein structure is to develop tools that accurately predict three-dimensional structures of proteins from their primary sequence information [58, 59]. Many of the best tools to date only go part of the way by using known three-dimensional structures from proteins which share similar primary sequence to model the possible structures of new proteins. This technology still has a long way to go, but the potential rewards would be enormous, allowing a genome sequence to be translated into targets for therapeutic intervention in si-lico, in relatively short periods of time. 

Sinz A. Chemical cross-linking and mass spectrometry for mapping three-dimensional structures of proteins and protein complexes. I. Mass. Spectrom. 2003 38 1225-1237. 

It is the sequence and types of amino acids and the way that they are folded that provides protein molecules with specific structure, activity, and function. Ionic charge, hydrogen bonding capability, and hydrophobicity are the major determinants for the resultant three-dimensional structure of protein molecules. The a-chain is twisted, folded, and formed into globular structures, a-helicies, and P-sheets based upon the side-chain amino acid sequence and weak intramolecular interactions such as hydrogen bonding between different parts of the peptide... 

Until quite recently, X-ray crystallography was the technique used almost exclusively to resolve the three-dimensional structure of proteins. As well as itself being technically challenging, a major limitation of X-ray crystallography is the requirement for the target protein to be in crystalline form. It has thus far proven difficult/impossible to induce the majority of proteins to crystallize. NMR is an analytical technique that can also be used to determine the three-dimensional structure of a molecule, and without the necessity for crystallization. For many years, even the most powerful NMR machines could resolve the three-dimensional structure of only relatively small proteins (less than 20-25 kDa). However, recent analytical advances now render it possible to analyse much larger proteins by this technique successfully. 

J. Greer, J. W. Erickson, J. J. Baldwin, M. D. Varney, Application of the Three Dimensional Structures of Protein Target Molecules in Structure-Based Drug Design ,./. Med. Chem. 1994, 37, 1035-1054. 

Sippl MJ. 1993. Recognition of errors in three-dimensional structures of proteins. Proteins 17(4) 355-362. 

Now we can ask what is likely to happen to the three-dimensional structure of a protein if we make a conservative replacement of one amino acid for another in the primary structnre. A conservative replacement involves, for example, substitution of one nonpolar amino acid for another, or replacement of one charged amino acid for another. Intnitively, one would expect that conservative replacements would have rather little effect on three-dimensional protein structure. If an isoleucine is replaced by a valine or leucine, the structnral modification is modest. The side chains of all of these amino acids are hydrophobic and will be content to sit in the molecnlar interior. This expectation is borne out in practice. We have noted earlier that there are many different molecnles of cytochrome c in nature, all of which serve the same basic function and all of which have similar three-dimensional structnres. We have also noted the species specificity of insulins among mammalian species. Here too we find a number of conservative changes in the primary structure of the hormone. Although there are exceptions, as a general rule conservative changes in the primary structnre of proteins are consistent with maintenance of the three-dimensional structures of proteins and the associated biological functions. 

Here are the key points, (a) DNA is the stuff of genes, (b) DNA is a sequence of nucleotides, each of which carries one of four possible symbols, (c) DNA is orgaiuzed into a sequence of genes, (d) Genes determine the sequence of amino acids in proteins, (e) The sequence of amino acids determines the three-dimensional structure of proteins, which, in turn (f) determines their biological properties. These, in turn (g) determine the nature of the cell. It follows that the sequence of bases in DNA is the ultimate repository of the information required to specify the uifique biochemical personality of the cell. 

We started out this section by emphasizing the importance of getting the amino acid sequence right. After all, the sequence determines the three-dimensional structure of proteins and that, in turn, is critical for function. Through multiple mechanisms, several of which we have mentioned, translation of the genetic code is remarkably accurate. The error rate is about 1 out of 10,000. Of course, many of the errors which... 

Evidently, resolution of the three-dimensional structures of proteins will aid in the design of rational approaches for constructing drug conjugates, as demonstrated by the above-mentioned examples. Evaluation of molecular structure at this level may prove to be one of the more successful approaches used in the design of recombinant drug conjugates. 

The findings that purely conformational changes in Mb will influence its reaction with antisera to the native protein (20,2 and the immunochemical results on numerous peptide fragmentsITave enabled us to conclude (20) that the antibody response is directed against the native three-dimensional structures of proteins. These conclusions, initially derived with early course antisera were shown, in more recent studies from this laboratory (22) to apply to antisera obtained up to a year after the initialTmmuni-zation. 

The guanidine group is a common structural feature in Nature, primarily due to its ability to stabilize the three-dimensional structure of proteins in enzymes through binding with anionic substrates. Roush and Walts (274) prepared the... 

Hydrogen bonds and ionic, hydrophobic (Greek, water-fearing ), and van der Waals interactions are individually weak, but collectively they have a very significant influence on the three-dimensional structures of proteins, nucleic acids, polysaccharides, and membrane lipids. 

In this chapter, we explore the three-dimensional structure of proteins, emphasizing five themes. First, the three-dimensional structure of a protein is determined by its amino acid sequence. Second, the function 116... 

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