3unt: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
[[ | ==tRNA-guanine transglycosylase E339Q mutant== | ||
<StructureSection load='3unt' size='340' side='right' caption='[[3unt]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3unt]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"achromobacter_anaerobium"_(sic)_shimwell_1937 "achromobacter anaerobium" (sic) shimwell 1937]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3UNT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3UNT FirstGlance]. <br> | |||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene><br> | |||
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1pud|1pud]], [[3gev|3gev]], [[3hfy|3hfy]]</td></tr> | |||
<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">tgt, ZMO0363 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=542 "Achromobacter anaerobium" (sic) Shimwell 1937])</td></tr> | |||
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/tRNA-guanine(34)_transglycosylase tRNA-guanine(34) transglycosylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.29 2.4.2.29] </span></td></tr> | |||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3unt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3unt OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3unt RCSB], [http://www.ebi.ac.uk/pdbsum/3unt PDBsum]</span></td></tr> | |||
<table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Interference with protein-protein interactions of interfaces larger than 1500 A2 by small drug-like molecules is notoriously difficult, particularly if targeting homodimers. The tRNA modifying enzyme Tgt is only functionally active as a homodimer. Thus, blocking Tgt dimerization is a promising strategy for drug therapy as this protein is key to the development of Shigellosis. Our goal was to identify hot-spot residues which, upon mutation, results in a predominantly monomeric state of Tgt. The detailed understanding of the spatial location and stability contribution of the individual interaction hot-spot residues and the plasticity of motifs involved in the interface formation is a crucial prerequisite for the rational identification of drug-like inhibitors addressing the respective dimerization interface. Using computational analyses, we identified hot-spot residues that contribute particularly to dimer stability: a cluster of hydrophobic and aromatic residues as well as several salt bridges. This in silico prediction led to the identification of a promising double mutant, which was validated experimentally. Native nano-ESI mass spectrometry showed that the dimerization of the suggested mutant is largely prevented resulting in a predominantly monomeric state. Crystal structure analysis and enzyme kinetics of the mutant variant further support the evidence for enhanced monomerization and provide first insights into the structural consequences of the dimer destabilization. (c) Proteins 2014;. (c) 2014 Wiley Periodicals, Inc. | |||
Hot spot analysis to dissect the functional protein-protein interface of a tRNA-modifying enzyme.,Jakobi S, Nguyen TX, Debaene F, Metz A, Sanglier-Cianferani S, Reuter K, Klebe G Proteins. 2014 Jun 28. doi: 10.1002/prot.24637. PMID:24975703<ref>PMID:24975703</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | |||
== | *[[TRNA-guanine transglycosylase|TRNA-guanine transglycosylase]] | ||
[[ | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Heine, A.]] | [[Category: Heine, A.]] | ||
[[Category: Jakobi, S.]] | [[Category: Jakobi, S.]] | ||
Revision as of 12:08, 16 July 2014
tRNA-guanine transglycosylase E339Q mutanttRNA-guanine transglycosylase E339Q mutant
Structural highlights
Publication Abstract from PubMedInterference with protein-protein interactions of interfaces larger than 1500 A2 by small drug-like molecules is notoriously difficult, particularly if targeting homodimers. The tRNA modifying enzyme Tgt is only functionally active as a homodimer. Thus, blocking Tgt dimerization is a promising strategy for drug therapy as this protein is key to the development of Shigellosis. Our goal was to identify hot-spot residues which, upon mutation, results in a predominantly monomeric state of Tgt. The detailed understanding of the spatial location and stability contribution of the individual interaction hot-spot residues and the plasticity of motifs involved in the interface formation is a crucial prerequisite for the rational identification of drug-like inhibitors addressing the respective dimerization interface. Using computational analyses, we identified hot-spot residues that contribute particularly to dimer stability: a cluster of hydrophobic and aromatic residues as well as several salt bridges. This in silico prediction led to the identification of a promising double mutant, which was validated experimentally. Native nano-ESI mass spectrometry showed that the dimerization of the suggested mutant is largely prevented resulting in a predominantly monomeric state. Crystal structure analysis and enzyme kinetics of the mutant variant further support the evidence for enhanced monomerization and provide first insights into the structural consequences of the dimer destabilization. (c) Proteins 2014;. (c) 2014 Wiley Periodicals, Inc. Hot spot analysis to dissect the functional protein-protein interface of a tRNA-modifying enzyme.,Jakobi S, Nguyen TX, Debaene F, Metz A, Sanglier-Cianferani S, Reuter K, Klebe G Proteins. 2014 Jun 28. doi: 10.1002/prot.24637. PMID:24975703[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||||||