2i8c: Difference between revisions

Revision as of 07:12, 4 May 2008

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

OverviewOverview

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 StructureAbout this Structure

2I8C is a Single protein structure of sequence from Staphylococcus aureus. Full crystallographic information is available from OCA.

ReferenceReference

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 Page seeded by OCA on Sun May 4 07:12:20 2008

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OCA

@@ Line 1: / Line 1: @@
 [[Image:2i8c.gif|left|200px]]
- {{Structure
+<!--
-|PDB= 2i8c |SIZE=350|CAPTION= <scene name='initialview01'>2i8c</scene>, resolution 2.46&Aring;
+The line below this paragraph, containing "STRUCTURE_2i8c", creates the "Structure Box" on the page.
-|SITE=
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=ADP:ADENOSINE-5&#39;-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>
+or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/D-alanine--D-alanine_ligase D-alanine--D-alanine ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.2.4 6.3.2.4] </span>
+or leave the SCENE parameter empty for the default display.
-|GENE= ddl ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1280 Staphylococcus aureus])
+-->
-|DOMAIN=
+{{STRUCTURE_2i8c|  PDB=2i8c  |  SCENE=  }}
-|RELATEDENTRY=[[2i80|2I80]], [[2i87|2I87]]
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2i8c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2i8c OCA], [http://www.ebi.ac.uk/pdbsum/2i8c PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2i8c RCSB]</span>
-}}
 '''Allosteric inhibition of Staphylococcus aureus D-alanine:D-alanine ligase revealed by crystallographic studies'''
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 [[Category: Marotti, K R.]]
 [[Category: Tomich, P K.]]
-[[Category: adp complex]]
+[[Category: Adp complex]]
-[[Category: d-alanine:d-alanine ligase]]
+[[Category: D-alanine:d-alanine ligase]]
-[[Category: staphylococcus aureus]]
+[[Category: Staphylococcus aureus]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 07:12:20 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:41:03 2008''