2hxm

From Proteopedia

(Difference between revisions)

Current revision

Complex of UNG2 and a small Molecule synthetic Inhibitor

Structural highlights

2hxm is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.3Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

UNG_HUMAN Defects in UNG are a cause of immunodeficiency with hyper-IgM type 5 (HIGM5) [MIM: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.^[1] ^[2]

Function

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

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Human nuclear uracil DNA glycosylase (UNG2) is a cellular DNA repair enzyme that is essential for a number of diverse biological phenomena ranging from antibody diversification to B-cell lymphomas and type-1 human immunodeficiency virus infectivity. During each of these processes, UNG2 recognizes uracilated DNA and excises the uracil base by flipping it into the enzyme active site. We have taken advantage of the extrahelical uracil recognition mechanism to build large small-molecule libraries in which uracil is tethered via flexible alkane linkers to a collection of secondary binding elements. This high-throughput synthesis and screening approach produced two novel uracil-tethered inhibitors of UNG2, the best of which was crystallized with the enzyme. Remarkably, this inhibitor mimics the crucial hydrogen bonding and electrostatic interactions previously observed in UNG2 complexes with damaged uracilated DNA. Thus, the environment of the binding site selects for library ligands that share these DNA features. This is a general approach to rapid discovery of inhibitors of enzymes that recognize extrahelical damaged bases.

Mimicking damaged DNA with a small molecule inhibitor of human UNG2.,Krosky DJ, Bianchet MA, Seiple L, Chung S, Amzel LM, Stivers JT Nucleic Acids Res. 2006;34(20):5872-9. Epub 2006 Oct 24. PMID:17062624^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Imai K, Slupphaug G, Lee WI, Revy P, Nonoyama S, Catalan N, Yel L, Forveille M, Kavli B, Krokan HE, Ochs HD, Fischer A, Durandy A. Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination. Nat Immunol. 2003 Oct;4(10):1023-8. Epub 2003 Sep 7. PMID:12958596 doi:http://dx.doi.org/10.1038/ni974
↑ Kavli B, Andersen S, Otterlei M, Liabakk NB, Imai K, Fischer A, Durandy A, Krokan HE, Slupphaug G. B cells from hyper-IgM patients carrying UNG mutations lack ability to remove uracil from ssDNA and have elevated genomic uracil. J Exp Med. 2005 Jun 20;201(12):2011-21. PMID:15967827 doi:10.1084/jem.20050042
↑ Krosky DJ, Bianchet MA, Seiple L, Chung S, Amzel LM, Stivers JT. Mimicking damaged DNA with a small molecule inhibitor of human UNG2. Nucleic Acids Res. 2006;34(20):5872-9. Epub 2006 Oct 24. PMID:17062624 doi:http://dx.doi.org/10.1093/nar/gkl747

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2hxm"

@@ Line 1: / Line 1: @@
-[[Image:2hxm.png|left|200px]]
-{{STRUCTURE_2hxm|  PDB=2hxm  |  SCENE=  }}
+==Complex of UNG2 and a small Molecule synthetic Inhibitor==
+<StructureSection load='2hxm' size='340' side='right'caption='[[2hxm]], [[Resolution|resolution]] 1.30&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2hxm]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2HXM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2HXM FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.3&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=302:4-[(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'>302</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2hxm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2hxm OCA], [https://pdbe.org/2hxm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2hxm RCSB], [https://www.ebi.ac.uk/pdbsum/2hxm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2hxm ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/UNG_HUMAN UNG_HUMAN] Defects in UNG are a cause of immunodeficiency with hyper-IgM type 5 (HIGM5) [MIM:[https://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 ==
+[https://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/hx/2hxm_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=2hxm ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Human nuclear uracil DNA glycosylase (UNG2) is a cellular DNA repair enzyme that is essential for a number of diverse biological phenomena ranging from antibody diversification to B-cell lymphomas and type-1 human immunodeficiency virus infectivity. During each of these processes, UNG2 recognizes uracilated DNA and excises the uracil base by flipping it into the enzyme active site. We have taken advantage of the extrahelical uracil recognition mechanism to build large small-molecule libraries in which uracil is tethered via flexible alkane linkers to a collection of secondary binding elements. This high-throughput synthesis and screening approach produced two novel uracil-tethered inhibitors of UNG2, the best of which was crystallized with the enzyme. Remarkably, this inhibitor mimics the crucial hydrogen bonding and electrostatic interactions previously observed in UNG2 complexes with damaged uracilated DNA. Thus, the environment of the binding site selects for library ligands that share these DNA features. This is a general approach to rapid discovery of inhibitors of enzymes that recognize extrahelical damaged bases.
-===Complex of UNG2 and a small Molecule synthetic Inhibitor===
+Mimicking damaged DNA with a small molecule inhibitor of human UNG2.,Krosky DJ, Bianchet MA, Seiple L, Chung S, Amzel LM, Stivers JT Nucleic Acids Res. 2006;34(20):5872-9. Epub 2006 Oct 24. PMID:17062624<ref>PMID:17062624</ref>
-{{ABSTRACT_PUBMED_17062624}}
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
-==About this Structure==
+<div class="pdbe-citations 2hxm" style="background-color:#fffaf0;"></div>
-[[2hxm]] is a 1 chain structure of [[DNA glycosylate]] with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2HXM OCA].
 ==See Also==
-*[[DNA glycosylate|DNA glycosylate]]
+*[[DNA glycosylase 3D structures|DNA glycosylase 3D structures]]
+== References ==
-==Reference==
+<references/>
-<ref group="xtra">PMID:017062624</ref><references group="xtra"/>
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Amzel, L M.]]
+[[Category: Large Structures]]
-[[Category: Bianchet, M A.]]
+[[Category: Amzel LM]]
-[[Category: Ghung, S.]]
+[[Category: Bianchet MA]]
-[[Category: Krosky, D J.]]
+[[Category: Ghung S]]
-[[Category: Seiple, L.]]
+[[Category: Krosky DJ]]
-[[Category: Stivers,J T.]]
+[[Category: Seiple L]]
-[[Category: Dna repair]]
+[[Category: Stivers JT]]
-[[Category: Hydrolase]]
-[[Category: Uracil]]
-[[Category: Uracil dna glycosylase]]

2hxm

From Proteopedia

Current revision

Complex of UNG2 and a small Molecule synthetic Inhibitor

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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