Three dimensional folding, protein

Figure 7.2 Schematic showing the relationship of the native antigen to the peptide mimic. The native antigen (a protein) is shown as a winding, twisted line, so as to represent a hypothetical three-dimensional structure. The peptide represents the antibody-binding epitope (shown in dotted lines) of the native antigen. The epitope can represent a linear sequence of the native protein. Alternatively, the epitope can be formed by amino acids that are not immediately adjacent to each other in the primary sequence but brought together by the three-dimensional folding of the protein. Adapted with permission from Sompuram et al.6...

In this section, the structure, function, and reactivity of amino acids, peptides, and proteins will be discussed with the goal of providing a foundation for successful derivatization. The interplay of amino acid functionality and the three-dimensional folding of polypeptide chains will be seen as forming the basis for protein activity. Understanding how the attachment of foreign molecules can affect this tenuous relationship, and thus alter protein function, ultimately will create a rational approach to protein chemistry and modification. 

Invent computer methods to predict the three-dimensional folded structure of a protein—and the pathway by which folding occurs—from its amino acid sequence, so information from the human genome can be translated into the encoded protein structures. 

The structural analysis of membrane-associated peptides comprises two steps (a) the elucidation of the three-dimensional fold of the peptide and (b) the determination of the membrane-peptide interface. We will use our results gained for the 36 amino acid residue neuropeptide Y (NPY) [83] to demonstrate the approaches that can be used. NPY regulates important pharmacological functions such as blood pressure, food intake or memory retention and hence has been subject of many investigations (for a review see Ref. [84]). It targets the so-called Y receptors that belong to the class of seven transmembrane receptors coupled to G-proteins (GPCRs). 

Scientists carry out searches on databases. Each EST of interest can be compared with sequences in proteins, and the degree of match can be determined. A technique called threading is used. This involves using data on three-dimensional (3D) protein structure, coupled with knowledge of the physicochemical properties of amino acids, to determine if the amino acid sequence is likely to fold in the same way as a sequence for which the structure is known. In this way, more information about the putative target protein can be assessed. 

In the past several years there has been an explosion of structural studies within the protein kinase family [1-8]. These studies, initiated by the crystal structure of Protein Kinase A [9-12] (CAPK) have shown that all members of the protein kinase family fold into a uniform three-dimensional catalytic core. Yet this uniform three-dimensional fold exhibits both different surface charges and at least two major conformations. 

Proteins spontaneously fold into their native conformation, with the primary structure of the protein dictating its three-dimensional structure. Protein folding is driven primarily by hydrophobic forces and proceeds through an ordered set of pathways. Accessory proteins, including protein disulfide isomerases, peptidyl prolyl cis-trans isomerases, and molecular chaperones, assist proteins to fold correctly in the cell. 

The determination of the secondary and tertiary structure—that is, the details of the three-dimensional folding of the polypeptide chain of a protein at high resolution—relies on one of two powerful techniques x-ray diffraction analysis of protein crystals and multidimensional high-field nuclear magnetic resonance (NMR) spectroscopy. Both methods provide very detailed structural in-... 

The sequence of amino acids in the long chain defines the primary structure of a protein. A secondary structure is determined when several residues, linked by hydrogen bonds, conform to a given combination (e.g., the a-helix, pleated sheet, and P-turns). Tertiary structure refers to the three-dimensional folded conformation of a protein. This is the biologically active conformation (crystal structure). A quaternary structure can result when two or more individual proteins assemble into two or more polypeptide chains. Conjugated proteins are complexes of proteins with other biomolecules, such as glycoproteins (sugar-proteins). 

The functional properties of proteins, like those of other biomolecules, are determined by their three-dimensional structures. Proteins possess an extremely important property a protein spontaneously folds into a welldefined and elaborate three-dimensional structure that is dictated entirely by the sequence of amino acids along its chain (Figure 1.6). The self-folding nature ofproteins constitutes the transition from the one-dimensional world of sequence information to the three-dimensional world of biological function. This marvelous ability of proteins to self assemble into complex... 

For chain molecules, such as peptides and proteins, the three-dimensional folding pattern is of great importance, and the shape characterization on the corresponding lower levels of resolution requires techniques different from those used for small molecules. For proteins this folding pattern has several, distinguishable levels of complexity. The primary structural arrangement of a protein is reflected in the sequence of amino acids. The peptide chain may coil up to form an a-helix, or it may form a structure called ji-strand, whose strands may... 

Describe two common shapes found in the three-dimensional folding of proteins. (24.1)... 

Manufacturing changes are more likely to affect the clinical profile of biological compounds than small chemical entities. Small changes in the three-dimensional folding, posttranslational modification or glycosylation of proteins can significantly... 

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