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[[Image:2i80.gif|left|200px]]
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{{STRUCTURE_2i80|  PDB=2i80  |  SCENE=  }}
'''Allosteric inhibition of Staphylococcus aureus D-alanine:D-alanine ligase revealed by crystallographic studies'''


==Allosteric inhibition of Staphylococcus aureus D-alanine:D-alanine ligase revealed by crystallographic studies==
<StructureSection load='2i80' size='340' side='right'caption='[[2i80]], [[Resolution|resolution]] 2.19&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2i80]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2I80 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2I80 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]] 2.19&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=G1L:3-CHLORO-2,2-DIMETHYL-N-[4-(TRIFLUOROMETHYL)PHENYL]PROPANAMIDE'>G1L</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=2i80 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2i80 OCA], [https://pdbe.org/2i80 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2i80 RCSB], [https://www.ebi.ac.uk/pdbsum/2i80 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2i80 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/DDL_STAAC DDL_STAAC] Cell wall formation (By similarity).
== 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/i8/2i80_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=2i80 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
D-alanine:D-alanine ligase (DDl) is an essential enzyme in bacterial cell wall biosynthesis and an important target for developing new antibiotics. It catalyzes the formation of D-alanine:D-alanine dipeptide, sequentially by using one D-alanine and one ATP as substrates for the first-half reaction, and a second D-alanine substrate to complete the reaction. Some gain of function DDl mutants can use an alternate second substrate, causing resistance to vancomycin, one of the last lines of defense against life-threatening Gram-positive infections. Here, we report the crystal structure of Staphylococcus aureus DDl (StaDDl) and its cocrystal structures with 3-chloro-2,2-dimethyl-N-[4(trifluoromethyl)phenyl]propanamide (inhibitor 1) (Ki=4 microM against StaDDl) and with ADP, one of the reaction products, at resolutions of 2.0, 2.2, and 2.6 A, respectively. The overall structure of StaDDl can be divided into three distinct domains. The inhibitor binds to a hydrophobic pocket at the interface of the first and the third domain. This inhibitor-binding pocket is adjacent to the first D-alanine substrate site but does not overlap with any substrate sites. An allosteric inhibition mechanism of StaDDl by this compound was proposed. The mechanism provides the basis for developing new antibiotics targeting D-alanine:D-alanine ligase. Because this compound only interacts with residues from the first D-alanine site, inhibitors with this binding mode potentially could overcome vancomycin resistance.


==Overview==
Allosteric inhibition of Staphylococcus aureus D-alanine:D-alanine ligase revealed by crystallographic studies.,Liu S, Chang JS, Herberg JT, Horng MM, Tomich PK, Lin AH, Marotti KR Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15178-83. Epub 2006 Oct 2. PMID:17015835<ref>PMID:17015835</ref>
D-alanine:D-alanine ligase (DDl) is an essential enzyme in bacterial cell wall biosynthesis and an important target for developing new antibiotics. It catalyzes the formation of D-alanine:D-alanine dipeptide, sequentially by using one D-alanine and one ATP as substrates for the first-half reaction, and a second D-alanine substrate to complete the reaction. Some gain of function DDl mutants can use an alternate second substrate, causing resistance to vancomycin, one of the last lines of defense against life-threatening Gram-positive infections. Here, we report the crystal structure of Staphylococcus aureus DDl (StaDDl) and its cocrystal structures with 3-chloro-2,2-dimethyl-N-[4(trifluoromethyl)phenyl]propanamide (inhibitor 1) (Ki=4 microM against StaDDl) and with ADP, one of the reaction products, at resolutions of 2.0, 2.2, and 2.6 A, respectively. The overall structure of StaDDl can be divided into three distinct domains. The inhibitor binds to a hydrophobic pocket at the interface of the first and the third domain. This inhibitor-binding pocket is adjacent to the first D-alanine substrate site but does not overlap with any substrate sites. An allosteric inhibition mechanism of StaDDl by this compound was proposed. The mechanism provides the basis for developing new antibiotics targeting D-alanine:D-alanine ligase. Because this compound only interacts with residues from the first D-alanine site, inhibitors with this binding mode potentially could overcome vancomycin resistance.


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
2I80 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2I80 OCA].
</div>
<div class="pdbe-citations 2i80" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
Allosteric inhibition of Staphylococcus aureus D-alanine:D-alanine ligase revealed by crystallographic studies., Liu S, Chang JS, Herberg JT, Horng MM, Tomich PK, Lin AH, Marotti KR, Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15178-83. Epub 2006 Oct 2. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17015835 17015835]
*[[D-alanine-D-alanine ligase 3D structures|D-alanine-D-alanine ligase 3D structures]]
[[Category: D-alanine--D-alanine ligase]]
== References ==
[[Category: Single protein]]
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Staphylococcus aureus]]
[[Category: Staphylococcus aureus]]
[[Category: Chang, J S.]]
[[Category: Chang JS]]
[[Category: Herberg, J T.]]
[[Category: Herberg JT]]
[[Category: Horng, M M.]]
[[Category: Horng M-M]]
[[Category: Lin, A H.]]
[[Category: Lin AH]]
[[Category: Liu, S.]]
[[Category: Liu S]]
[[Category: Marotti, K R.]]
[[Category: Marotti KR]]
[[Category: Tomich, P K.]]
[[Category: Tomich PK]]
[[Category: Protein-inhibitor complex]]
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 07:11:36 2008''

Latest revision as of 13:07, 30 August 2023

Allosteric inhibition of Staphylococcus aureus D-alanine:D-alanine ligase revealed by crystallographic studiesAllosteric inhibition of Staphylococcus aureus D-alanine:D-alanine ligase revealed by crystallographic studies

Structural highlights

2i80 is a 2 chain structure with sequence from Staphylococcus aureus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.19Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DDL_STAAC Cell wall formation (By similarity).

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

D-alanine:D-alanine ligase (DDl) is an essential enzyme in bacterial cell wall biosynthesis and an important target for developing new antibiotics. It catalyzes the formation of D-alanine:D-alanine dipeptide, sequentially by using one D-alanine and one ATP as substrates for the first-half reaction, and a second D-alanine substrate to complete the reaction. Some gain of function DDl mutants can use an alternate second substrate, causing resistance to vancomycin, one of the last lines of defense against life-threatening Gram-positive infections. Here, we report the crystal structure of Staphylococcus aureus DDl (StaDDl) and its cocrystal structures with 3-chloro-2,2-dimethyl-N-[4(trifluoromethyl)phenyl]propanamide (inhibitor 1) (Ki=4 microM against StaDDl) and with ADP, one of the reaction products, at resolutions of 2.0, 2.2, and 2.6 A, respectively. The overall structure of StaDDl can be divided into three distinct domains. The inhibitor binds to a hydrophobic pocket at the interface of the first and the third domain. This inhibitor-binding pocket is adjacent to the first D-alanine substrate site but does not overlap with any substrate sites. An allosteric inhibition mechanism of StaDDl by this compound was proposed. The mechanism provides the basis for developing new antibiotics targeting D-alanine:D-alanine ligase. Because this compound only interacts with residues from the first D-alanine site, inhibitors with this binding mode potentially could overcome vancomycin resistance.

Allosteric inhibition of Staphylococcus aureus D-alanine:D-alanine ligase revealed by crystallographic studies.,Liu S, Chang JS, Herberg JT, Horng MM, Tomich PK, Lin AH, Marotti KR Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15178-83. Epub 2006 Oct 2. PMID:17015835[1]

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

See Also

References

  1. ↑ Liu S, Chang JS, Herberg JT, Horng MM, Tomich PK, Lin AH, Marotti KR. Allosteric inhibition of Staphylococcus aureus D-alanine:D-alanine ligase revealed by crystallographic studies. Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15178-83. Epub 2006 Oct 2. PMID:17015835

2i80, resolution 2.19Å

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