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<StructureSection load='' size='350' side='right' scene='Book:Structural_Proteomics_and_its_Impact_on_the_Life_Sciences:6/Cv/2' caption=''> == Chapter 6: [http://www.worldscientific.com/worldscibooks/10.1142/6619 The Contribution of Structural Proteomics to Understanding the Function of Hypothetical Proteins] == <big>Michael D. Suits, Allan Matte, Zongchao Jia and Miroslaw Cygler</big> <ref>Suits, M. D., Matte, A., Jia, Z. & Cygler, M. (2008). The Contribution of Structural Proteomics to Understanding the Function of Hypothetical Proteins. In Structural Proteomics and its Impact on the Life Sciences (Sussman, J. L. & Silman, I., eds.), pp. 135-151. World Scientific Publishing Company, London.</ref> <hr/> <b>Molecular Tour</b><br> Structural Genomics efforts throughout the world have led to the development of high-throughput (HTP) techniques from genes to 3D structures. These HTP methods have yield thousands of new structures, many of which are from hypothetical proteins, with less than 30% sequence identity to a protein of known 3D structure, and are unknown function. In order to attempt to make functional assignments for these proteins, The Montreal-Kingston Bacterial Structural Genomics Initiative <ref name="Link">[http://euler.bri.nrc.ca/brimsg/bsgi.html http://euler.bri.nrc.ca/brimsg/bsgi.html]</ref> has been utilizing 3D structural information of these newly determined proteins. Here are illustrations of several such examples. '''A quinate/shikimate dehydrogenase from Escherichia coli - YdiB''' <scene name='Book:Structural_Proteomics_and_its_Impact_on_the_Life_Sciences:6/Cv/3'>YdiB, an E. coli protein, was annotated as a putative shikimate dehydrogenase</scene> ([[1o9b]] <ref name="Michel">PMID:12637497</ref>, <font color='magenta'><b>monomer A is in magenta</b></font>, <span style="color:cyan;background-color:black;font-weight:bold;">monomer B is in cyan</span>), as it possessed 28% sequence identity to E. coli AroE, a characterized shikimate dehydrogenase<ref name="Chaudhuri">PMID:3883995</ref>. <scene name='Book:Structural_Proteomics_and_its_Impact_on_the_Life_Sciences:6/Cv/4'>The structure of E. coli YdiB revealed interesting similarities and differences to E. coli AroE</scene> ([[1nyt]]). <font color='magenta'><b>YdiB is in magenta</b></font>, <span style="color:yellow;background-color:black;font-weight:bold;">AroE is in yellow</span>, <span style="color:lime;background-color:black;font-weight:bold;">carbon atoms of NAD and NADP are in green</span>. <scene name='Book:Structural_Proteomics_and_its_Impact_on_the_Life_Sciences:6/Cv/5'>Click here to see animation of this scene</scene>. Both enzymes share similar folds, contain signature motifs indicative of dinucleotide (NAD+, NADP+) binding, and while AroE is a monomer, the crystal structure of E. coli YdiB revealed a dimer <ref name="Michel">PMID:12637497</ref>. <scene name='Book:Structural_Proteomics_and_its_Impact_on_the_Life_Sciences:6/Cv/7'>The mode of dimerization of YdiB is unusual</scene>, as it involves a relatively <scene name='Book:Structural_Proteomics_and_its_Impact_on_the_Life_Sciences:6/Cv/6'>small surface of each monomer</scene>, but is consistent with the molecular weight determined by size exclusion chromatography. Both enzymes consist of two &#945;/&#946; domains, with the C-terminal domain adopting a canonical Rossmann fold topology, consistent with dinucleotide binding. '''Escherichia coli Proteins Associated With Heme Metabolism''' At the initiation of our investigation ChuS, from Shigella dysenteriae ([[1u9t]]), was known only as a protein up-regulated under low iron conditions, responsible for the prevention of heme toxicity. It showed low sequence homology to know 3D structures and thus there was no clear function for this protein. <scene name='Book:Structural_Proteomics_and_its_Impact_on_the_Life_Sciences:6/Cv/8'>The structure of ChuS revealed a central core of two</scene>, 9-stranded anti-parallel &#946;-sheets, each flanked at its N-terminus by one pair of parallel &#945;-helices and at its C-terminus by a set of three &#945;-helices in an helix-loop-helix-loop-helix configuration. <font color='red'><b>N-</b></font> and <font color='blue'><b>C-terminal</b></font> domains are colored <font color='red'><b>red</b></font> and <font color='blue'><b>blue</b></font>, respectively. The structure clearly indicated that ChuS arose by gene duplication, as can be seen by <scene name='Book:Structural_Proteomics_and_its_Impact_on_the_Life_Sciences:6/Cv/9'>superimposing the N and C terminal domains</scene> on each other resulting in an RMS of of 2.1 Å. Based on the ChuS site directed mutation studies were carried out that indicated that demonstrate in the <scene name='Book:Structural_Proteomics_and_its_Impact_on_the_Life_Sciences:6/Cv/13'>ChuS-heme complex</scene> ([[2hq2]], <font color='indigo'><b>N-</b></font> and <span style="color:lime;background-color:black;font-weight:bold;">C-terminal</span> domains are colored <font color='indigo'><b>indigo</b></font> and <span style="color:lime;background-color:black;font-weight:bold;">green</span>, respectively) that <scene name='Book:Structural_Proteomics_and_its_Impact_on_the_Life_Sciences:6/Cv/14'>His193 is responsible for axial ligation of heme, and that Arg100 further stabilizes the heme group from the medial side of the protein via two water molecules</scene>. <span style="color:yellow;background-color:black;font-weight:bold;">Carbon atoms of heme are in yellow</span>, <font color='magenta'><b>Arg100 and His193 are in magenta</b></font>, and <font color='red'><b>water molecules are in red</b></font>. It is also interesting to note that the <scene name='Book:Structural_Proteomics_and_its_Impact_on_the_Life_Sciences:6/Cv/12'>dimer structure of ChuX</scene> ([[2ovi]]) displays a surprising degree of similarity to the monomer structures of two other heme utilization operon proteins, E. coli ChuS and Y. enterocolitica HemS, both of which have an internal domain repeat. The conserved <span style="color:yellow;background-color:black;font-weight:bold;">His65</span> and <font color='red'><b>His98</b></font> are in <span style="color:yellow;background-color:black;font-weight:bold;">yellow</span> and <font color='red'><b>red</b></font>, respectively. </StructureSection> <references/> __NOEDITSECTION__

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