2i80: Difference between revisions

Revision as of 18:50, 21 February 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

2I80 is a Single protein structure of sequence from Staphylococcus aureus with as ligand. Active as D-alanine--D-alanine ligase, with EC number 6.3.2.4 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 Thu Feb 21 17:50:00 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
-[[Image:2i80.gif|left|200px]]<br /><applet load="2i80" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:2i80.gif|left|200px]]<br /><applet load="2i80" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="2i80, resolution 2.19&Aring;" />
 '''Allosteric inhibition of Staphylococcus aureus D-alanine:D-alanine ligase revealed by crystallographic studies'''<br />
 ==Overview==
-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.
+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==
-I80 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus] with G1L as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2I80 OCA].
+I80 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus] with <scene name='pdbligand=G1L:'>G1L</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2I80 OCA].
 ==Reference==
@@ Line 14: / Line 14: @@
 [[Category: Single protein]]
 [[Category: Staphylococcus aureus]]
-[[Category: Chang, J.S.]]
+[[Category: Chang, J S.]]
-[[Category: Herberg, J.T.]]
+[[Category: Herberg, J T.]]
-[[Category: Horng, M.M.]]
+[[Category: Horng, M M.]]
-[[Category: Lin, A.H.]]
+[[Category: Lin, A H.]]
 [[Category: Liu, S.]]
-[[Category: Marotti, K.R.]]
+[[Category: Marotti, K R.]]
-[[Category: Tomich, P.K.]]
+[[Category: Tomich, P K.]]
 [[Category: G1L]]
 [[Category: protein-inhibitor complex]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 12:11:07 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:50:00 2008''