View source for 3fcf


==Complex of UNG2 and a fragment-based designed inhibitor==
<StructureSection load='3fcf' size='340' side='right' caption='[[3fcf]], [[Resolution|resolution]] 1.84&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3fcf]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3FCF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3FCF FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FCF:3-[(1E,7E)-8-(2,6-DIOXO-1,2,3,6-TETRAHYDROPYRIMIDIN-4-YL)-3,6-DIOXA-2,7-DIAZAOCTA-1,7-DIEN-1-YL]BENZOIC+ACID'>FCF</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3fci|3fci]], [[3fck|3fck]], [[3fcl|3fcl]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">UNG, DGU, UNG1, UNG15 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3fcf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fcf OCA], [http://pdbe.org/3fcf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3fcf RCSB], [http://www.ebi.ac.uk/pdbsum/3fcf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3fcf ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/UNG_HUMAN UNG_HUMAN]] Defects in UNG are a cause of immunodeficiency with hyper-IgM type 5 (HIGM5) [MIM:[http://omim.org/entry/608106 608106]]. A rare immunodeficiency syndrome characterized by normal or elevated serum IgM levels with absence of IgG, IgA, and IgE. It results in a profound susceptibility to bacterial infections.<ref>PMID:12958596</ref> <ref>PMID:15967827</ref>  
== Function ==
[[http://www.uniprot.org/uniprot/UNG_HUMAN UNG_HUMAN]] Excises uracil residues from the DNA which can arise as a result of misincorporation of dUMP residues by DNA polymerase or due to deamination of cytosine. 
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/fc/3fcf_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3fcf ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The linking together of molecular fragments that bind to adjacent sites on an enzyme can lead to high-affinity inhibitors. Ideally, this strategy would use linkers that do not perturb the optimal binding geometries of the fragments and do not have excessive conformational flexibility that would increase the entropic penalty of binding. In reality, these aims are seldom realized owing to limitations in linker chemistry. Here we systematically explore the energetic and structural effects of rigid and flexible linkers on the binding of a fragment-based inhibitor of human uracil DNA glycosylase. Analysis of the free energies of binding in combination with cocrystal structures shows that the flexibility and strain of a given linker can have a substantial impact on binding affinity even when the binding fragments are optimally positioned. Such effects are not apparent from inspection of structures and underscore the importance of linker optimization in fragment-based drug discovery efforts.

Impact of linker strain and flexibility in the design of a fragment-based inhibitor.,Chung S, Parker JB, Bianchet M, Amzel LM, Stivers JT Nat Chem Biol. 2009 Jun;5(6):407-13. Epub 2009 Apr 26. PMID:19396178<ref>PMID:19396178</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3fcf" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Amzel, L M]]
[[Category: Bianchet, M A]]
[[Category: Chung, S]]
[[Category: Parker, J B]]
[[Category: Stivers, J T]]
[[Category: Alternative splicing]]
[[Category: Disease mutation]]
[[Category: Dna damage]]
[[Category: Dna repair]]
[[Category: Glycosidase]]
[[Category: Host-virus interaction]]
[[Category: Hydrolase]]
[[Category: Mitochondrion]]
[[Category: Nucleus]]
[[Category: Phosphoprotein]]
[[Category: Transit peptide]]
[[Category: Uracil]]
[[Category: Uracil dna glycosylase]]