5z4h: Difference between revisions

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'''Unreleased structure'''


The entry 5z4h is ON HOLD until Paper Publication
==Bacterial GyrB ATPase domain in complex with a chemical fragment==
<StructureSection load='5z4h' size='340' side='right' caption='[[5z4h]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5z4h]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5Z4H OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5Z4H FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=A8K:4-(4-hydroxyphenyl)sulfanylphenol'>A8K</scene>, <scene name='pdbligand=AX7:1H-BENZIMIDAZOL-2-AMINE'>AX7</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/DNA_topoisomerase_(ATP-hydrolyzing) DNA topoisomerase (ATP-hydrolyzing)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.99.1.3 5.99.1.3] </span></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=5z4h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5z4h OCA], [http://pdbe.org/5z4h PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5z4h RCSB], [http://www.ebi.ac.uk/pdbsum/5z4h PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5z4h ProSAT]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/GYRB_ECOLI GYRB_ECOLI]] DNA gyrase negatively supercoils closed circular double-stranded DNA in an ATP-dependent manner and also catalyzes the interconversion of other topological isomers of double-stranded DNA rings, including catenanes and knotted rings.<ref>PMID:12051843</ref> <ref>PMID:18642932</ref> <ref>PMID:20675723</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Discovery of new drug binding sites on well-established targets is of great interest as it facilitates the design of new mechanistic inhibitors to overcome the acquired drug resistance. Small chemical fragments can easily enter and bind to the cavities on the protein surface. Thus, they can be used to probe new druggable pockets in proteins. DNA gyrase plays indispensable roles in DNA replication, and both its GyrA and GyrB subunits are clinically validated antibacterial targets. New mechanistic GyrB inhibitors are urgently desired since the withdrawal of novobiocin from the market by the FDA due to its reduced efficiency and other reasons. Here, a fragment library was screened against the E. coli GyrB ATPase domain by combining affinity- and bioactivity-based approaches. The following X-ray crystallographic efforts were made to determine the cocrystal structures of GyrB with ten fragment hits, and three different binding modes were disclosed. Fortunately, a hydrophobic pocket which is previously unknown was identified by two fragments. Fragments that bind to this pocket were shown to inhibit the ATPase activity as well as the DNA topological transition activity of DNA gyrase in vitro. A set of fragment analogs were screened to explore the binding capacity of this pocket and identify the better starting fragments for lead development. Phylogenetic analysis revealed that this pocket is conserved in most Gram-negative and also many Gram-positive human pathogenic bacteria, implying a broad-spectrum antibacterial potential and a lower risk of mutation. Thus, the novel druggable pocket and the starting fragments provide a novel basis for designing new GyrB-targeting therapeutics.


Authors: Huang, X., Zhou, H.
Identification of an auxiliary druggable pocket in the DNA gyrase ATPase domain using fragment probes.,Huang X, Guo J, Liu Q, Gu Q, Xu J, Zhou H Medchemcomm. 2018 Jul 4;9(10):1619-1629. doi: 10.1039/c8md00148k. eCollection, 2018 Oct 1. PMID:30429968<ref>PMID:30429968</ref>


Description: Bacterial GyrB ATPase domain in complex with a chemical fragment
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
<div class="pdbe-citations 5z4h" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Huang, X]]
[[Category: Zhou, H]]
[[Category: Zhou, H]]
[[Category: Huang, X]]
[[Category: Antibacterial]]
[[Category: Dna topoisomerase]]
[[Category: Drug target]]
[[Category: Fragment-base lead discovery]]
[[Category: Isomerase]]

Revision as of 09:40, 12 December 2018

Bacterial GyrB ATPase domain in complex with a chemical fragmentBacterial GyrB ATPase domain in complex with a chemical fragment

Structural highlights

5z4h is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, ,
Activity:DNA topoisomerase (ATP-hydrolyzing), with EC number 5.99.1.3
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[GYRB_ECOLI] DNA gyrase negatively supercoils closed circular double-stranded DNA in an ATP-dependent manner and also catalyzes the interconversion of other topological isomers of double-stranded DNA rings, including catenanes and knotted rings.[1] [2] [3]

Publication Abstract from PubMed

Discovery of new drug binding sites on well-established targets is of great interest as it facilitates the design of new mechanistic inhibitors to overcome the acquired drug resistance. Small chemical fragments can easily enter and bind to the cavities on the protein surface. Thus, they can be used to probe new druggable pockets in proteins. DNA gyrase plays indispensable roles in DNA replication, and both its GyrA and GyrB subunits are clinically validated antibacterial targets. New mechanistic GyrB inhibitors are urgently desired since the withdrawal of novobiocin from the market by the FDA due to its reduced efficiency and other reasons. Here, a fragment library was screened against the E. coli GyrB ATPase domain by combining affinity- and bioactivity-based approaches. The following X-ray crystallographic efforts were made to determine the cocrystal structures of GyrB with ten fragment hits, and three different binding modes were disclosed. Fortunately, a hydrophobic pocket which is previously unknown was identified by two fragments. Fragments that bind to this pocket were shown to inhibit the ATPase activity as well as the DNA topological transition activity of DNA gyrase in vitro. A set of fragment analogs were screened to explore the binding capacity of this pocket and identify the better starting fragments for lead development. Phylogenetic analysis revealed that this pocket is conserved in most Gram-negative and also many Gram-positive human pathogenic bacteria, implying a broad-spectrum antibacterial potential and a lower risk of mutation. Thus, the novel druggable pocket and the starting fragments provide a novel basis for designing new GyrB-targeting therapeutics.

Identification of an auxiliary druggable pocket in the DNA gyrase ATPase domain using fragment probes.,Huang X, Guo J, Liu Q, Gu Q, Xu J, Zhou H Medchemcomm. 2018 Jul 4;9(10):1619-1629. doi: 10.1039/c8md00148k. eCollection, 2018 Oct 1. PMID:30429968[4]

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

References

  1. Noble CG, Maxwell A. The role of GyrB in the DNA cleavage-religation reaction of DNA gyrase: a proposed two metal-ion mechanism. J Mol Biol. 2002 Apr 26;318(2):361-71. PMID:12051843 doi:http://dx.doi.org/10.1016/S0022-2836(02)00049-9
  2. Sissi C, Chemello A, Vazquez E, Mitchenall LA, Maxwell A, Palumbo M. DNA gyrase requires DNA for effective two-site coordination of divalent metal ions: further insight into the mechanism of enzyme action. Biochemistry. 2008 Aug 19;47(33):8538-45. doi: 10.1021/bi800480j. Epub 2008 Jul, 22. PMID:18642932 doi:http://dx.doi.org/10.1021/bi800480j
  3. Schoeffler AJ, May AP, Berger JM. A domain insertion in Escherichia coli GyrB adopts a novel fold that plays a critical role in gyrase function. Nucleic Acids Res. 2010 Jul 31. PMID:20675723 doi:10.1093/nar/gkq665
  4. Huang X, Guo J, Liu Q, Gu Q, Xu J, Zhou H. Identification of an auxiliary druggable pocket in the DNA gyrase ATPase domain using fragment probes. Medchemcomm. 2018 Jul 4;9(10):1619-1629. doi: 10.1039/c8md00148k. eCollection, 2018 Oct 1. PMID:30429968 doi:http://dx.doi.org/10.1039/c8md00148k

5z4h, resolution 2.00Å

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