Proteins integral three-dimensional structure

Because the number of protein three-dimensional structures completed is relatively small, much of our understanding of the metal center structures comes from studies on inorganic model compounds. Although it is beyond the scope of this chapter to discuss these compounds separately, we have integrated some of the results in our discussion of the relevant protein structures. 

The development of COX-2-specific inhibitors has been helped immensely by knowledge of the detailed three-dimensional structures of COX-1 and COX-2 (Fig. 1). Both proteins are homodimers. Each monomer (A/, 70,000) has an amphipathic domain that penetrates but does not span the ER this anchors the enzyme on the lumenal side of the ER (a very unusual topology—generally the hydrophobic regions of integral membrane proteins span the entire bilayer). Both catalytic sites are on the globular domain protruding into the ER lumen. 

A three-dimensional structure also has been elucidated for bacteriorhodopsin, an integral membrane protein of the halophilic (salt-loving) bacterium Halobacterium halobium. This protein has been studied intensively because of its remarkable activity as a light-driven proton pump (see chapter 14). It forms well-ordered arrays in two-dimensional sheets that can be studied by electron diffraction. Measurements of the diffraction patterns show clearly that bacteriorhodopsin has seven transmembrane helices (fig. 17.12). 

Gowri VS, Pandit SB, Karthik PS et al (2003) Integration of related sequences with protein three-dimensional structural families in an updated version of PALI database. Nucleic Acids Res 31 486-488... 

The a subunit is the most essential component of an ion channel. It is an integral membrane protein that requires a phospholipid environment to maintain a functional three-dimensional structure. Most a subunits are capable of forming functional channels when expressed alone in an artificial system, but they are often associated in native systems with transmembrane or cytosolic auxiliary subunits that modulate and fine-tune the properties of the channel. It is important to note that ion channel subunits often co-assemble in a tissue-specific manner and sometimes the expression patterns of individual subunits may be altered in disease. Therefore, when one is developing an assay using a heterologously expressed ion channel target, it is always preferable to employ a combination of subunits appropriate to the tissue and/or disease of interest. 

A way to test these hypotheses directly would be to examine by X-ray crystallography or high resolution nuclear magnetic resonance (NMR) spectroscopy, the three-dimensional structure of the peptide-protein complexes. However, examination of the high resolution structure of integral membrane proteins has turned out to be very difficult, not only because of their reasonably large size (40-80... 

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