3fck: Difference between revisions

Latest revision as of 00:31, 28 December 2023

Complex of UNG2 and a fragment-based design inhibitor

Structural highlights

3fck 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 1.64Å
Ligands:	FCK
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

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^[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:https://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
↑ Chung S, Parker JB, Bianchet M, Amzel LM, Stivers JT. Impact of linker strain and flexibility in the design of a fragment-based inhibitor. Nat Chem Biol. 2009 Jun;5(6):407-13. Epub 2009 Apr 26. PMID:19396178 doi:10.1038/nchembio.163

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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:https://dx.doi.org/10.1038/ni974

[2] 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

[3] Chung S, Parker JB, Bianchet M, Amzel LM, Stivers JT. Impact of linker strain and flexibility in the design of a fragment-based inhibitor. Nat Chem Biol. 2009 Jun;5(6):407-13. Epub 2009 Apr 26. PMID:19396178 doi:10.1038/nchembio.163

[1]

[2]

[3]

@@ Line 3: / Line 3: @@
 <StructureSection load='3fck' size='340' side='right'caption='[[3fck]], [[Resolution|resolution]] 1.64&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3fck]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3FCK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3FCK FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3fck]] 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=3FCK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3FCK FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FCK:3-({[3-({[(1E)-(2,6-DIOXO-1,2,3,6-TETRAHYDROPYRIMIDIN-4-YL)METHYLIDENE]AMINO}OXY)PROPYL]AMINO}METHYL)BENZOIC+ACID'>FCK</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.64&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3fcf|3fcf]], [[3fci|3fci]], [[3fcl|3fcl]]</div></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FCK:3-({[3-({[(1E)-(2,6-DIOXO-1,2,3,6-TETRAHYDROPYRIMIDIN-4-YL)METHYLIDENE]AMINO}OXY)PROPYL]AMINO}METHYL)BENZOIC+ACID'>FCK</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">UNG, DGU, UNG1, UNG15 ([https://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'>[https://proteopedia.org/fgij/fg.htm?mol=3fck FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fck OCA], [https://pdbe.org/3fck PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3fck RCSB], [https://www.ebi.ac.uk/pdbsum/3fck PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3fck 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>
+[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.
+[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]]
@@ Line 39: / Line 38: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Amzel, L M]]
+[[Category: Amzel LM]]
-[[Category: Bianchet, M A]]
+[[Category: Bianchet MA]]
-[[Category: Chung, S]]
+[[Category: Chung S]]
-[[Category: Parker, J B]]
+[[Category: Parker JB]]
-[[Category: Stivers, J T]]
+[[Category: Stivers JT]]
-[[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]]

3fck: Difference between revisions

Latest revision as of 00:31, 28 December 2023

Complex of UNG2 and a fragment-based design inhibitor

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools