1cw2: Difference between revisions

Revision as of 13:10, 21 February 2008

CRYSTAL STRUCTURE OF THE COMPLEX OF BACTERIAL TRYPTOPHAN SYNTHASE WITH THE TRANSITION STATE ANALOGUE INHIBITOR 4-(2-HYDROXYPHENYLSULFINYL)-BUTYLPHOSPHONIC ACID

OverviewOverview

In an effort to use a structure-based approach for the design of new herbicides, the crystal structures of complexes of tryptophan synthase with a series of phosphonate enzyme inhibitors were determined at 2.3 A or higher resolution. These inhibitors were designed to mimic the transition state formed during the alpha-reaction of the enzyme and, as expected, have affinities much greater than that of the natural substrate indole-3-glycerol phosphate or its nonhydrolyzable analogue indole propanol phosphate (IPP). These inhibitors are ortho-substituted arylthioalkylphosphonate derivatives that have an sp(3)-hybridized sulfur atom, designed to mimic the putative tetrahedral transition state at the C3 atom of the indole, and lack the C2 atom to allow for higher conformational flexibility. Overall, the inhibitors bind in a fashion similar to that of IPP. Glu-49 and Phe-212 are the two active site residues whose conformation changes upon inhibitor binding. A very short hydrogen bond between a phosphonate oxygen and the Ser-235 hydroxyl oxygen may be responsible for stabilization of the enzyme-inhibitor complexes. Implications for the mechanism of catalysis as well as directions for more potent inhibitors are discussed.

About this StructureAbout this Structure

1CW2 is a Protein complex structure of sequences from Salmonella typhimurium with , and as ligands. Active as Tryptophan synthase, with EC number 4.2.1.20 Full crystallographic information is available from OCA.

ReferenceReference

Crystallographic studies of phosphonate-based alpha-reaction transition-state analogues complexed to tryptophan synthase., Sachpatzidis A, Dealwis C, Lubetsky JB, Liang PH, Anderson KS, Lolis E, Biochemistry. 1999 Sep 28;38(39):12665-74. PMID:10504236

Page seeded by OCA on Thu Feb 21 12:10:26 2008

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

OCA

@@ Line 1: / Line 1: @@
-[[Image:1cw2.gif|left|200px]]<br /><applet load="1cw2" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1cw2.gif|left|200px]]<br /><applet load="1cw2" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1cw2, resolution 2.0&Aring;" />
 '''CRYSTAL STRUCTURE OF THE COMPLEX OF BACTERIAL TRYPTOPHAN SYNTHASE WITH THE TRANSITION STATE ANALOGUE INHIBITOR 4-(2-HYDROXYPHENYLSULFINYL)-BUTYLPHOSPHONIC ACID'''<br />
 ==Overview==
-In an effort to use a structure-based approach for the design of new, herbicides, the crystal structures of complexes of tryptophan synthase, with a series of phosphonate enzyme inhibitors were determined at 2.3 A or, higher resolution. These inhibitors were designed to mimic the transition, state formed during the alpha-reaction of the enzyme and, as expected, have affinities much greater than that of the natural substrate, indole-3-glycerol phosphate or its nonhydrolyzable analogue indole, propanol phosphate (IPP). These inhibitors are ortho-substituted, arylthioalkylphosphonate derivatives that have an sp(3)-hybridized sulfur, atom, designed to mimic the putative tetrahedral transition state at the, C3 atom of the indole, and lack the C2 atom to allow for higher, conformational flexibility. Overall, the inhibitors bind in a fashion, similar to that of IPP. Glu-49 and Phe-212 are the two active site, residues whose conformation changes upon inhibitor binding. A very short, hydrogen bond between a phosphonate oxygen and the Ser-235 hydroxyl oxygen, may be responsible for stabilization of the enzyme-inhibitor complexes., Implications for the mechanism of catalysis as well as directions for more, potent inhibitors are discussed.
+In an effort to use a structure-based approach for the design of new herbicides, the crystal structures of complexes of tryptophan synthase with a series of phosphonate enzyme inhibitors were determined at 2.3 A or higher resolution. These inhibitors were designed to mimic the transition state formed during the alpha-reaction of the enzyme and, as expected, have affinities much greater than that of the natural substrate indole-3-glycerol phosphate or its nonhydrolyzable analogue indole propanol phosphate (IPP). These inhibitors are ortho-substituted arylthioalkylphosphonate derivatives that have an sp(3)-hybridized sulfur atom, designed to mimic the putative tetrahedral transition state at the C3 atom of the indole, and lack the C2 atom to allow for higher conformational flexibility. Overall, the inhibitors bind in a fashion similar to that of IPP. Glu-49 and Phe-212 are the two active site residues whose conformation changes upon inhibitor binding. A very short hydrogen bond between a phosphonate oxygen and the Ser-235 hydroxyl oxygen may be responsible for stabilization of the enzyme-inhibitor complexes. Implications for the mechanism of catalysis as well as directions for more potent inhibitors are discussed.
 ==About this Structure==
-CW2 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Salmonella_typhimurium Salmonella typhimurium] with NA, PLP and HSP as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Tryptophan_synthase Tryptophan synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.2.1.20 4.2.1.20] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1CW2 OCA].
+CW2 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Salmonella_typhimurium Salmonella typhimurium] with <scene name='pdbligand=NA:'>NA</scene>, <scene name='pdbligand=PLP:'>PLP</scene> and <scene name='pdbligand=HSP:'>HSP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Tryptophan_synthase Tryptophan synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.2.1.20 4.2.1.20] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1CW2 OCA].
 ==Reference==
@@ Line 14: / Line 14: @@
 [[Category: Salmonella typhimurium]]
 [[Category: Tryptophan synthase]]
-[[Category: Anderson, K.S.]]
+[[Category: Anderson, K S.]]
 [[Category: Dealwis, C.]]
-[[Category: Liang, P.H.]]
+[[Category: Liang, P H.]]
 [[Category: Lolis, E.]]
-[[Category: Lubetsky, J.B.]]
+[[Category: Lubetsky, J B.]]
 [[Category: Sachpatzidis, A.]]
 [[Category: HSP]]
@@ Line 26: / Line 26: @@
 [[Category: enzyme-inhibitor complex]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 12:47:52 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:10:26 2008''