1cps: Difference between revisions

Revision as of 13:08, 21 February 2008

STRUCTURAL COMPARISON OF SULFODIIMINE AND SULFONAMIDE INHIBITORS IN THEIR COMPLEXES WITH ZINC ENZYMES

OverviewOverview

The three-dimensional structure of (L(-)-2-carboxy-3-phenylpropyl) methylsulfodiimine in its complex with the zinc metalloenzyme carboxypeptidase A has been determined at 2.25-A resolution by x-ray crystallographic methods. This is the first example of a sulfodiimine-containing inhibitor binding to a zinc enzyme, and the structure of the enzyme-inhibitor complex reveals that the tetrahedral sulfodiimine group coordinates to the active site zinc ion in unidentate fashion. The zinc-coordinated nitrogen atom of the sulfodiimine group is also within hydrogen bonding distance to active site base Glu-270; presumably, the sulfodiimine is ionized and accepts a hydrogen bond from protonated Glu-270. The other sulfodiimine nitrogen accepts a hydrogen bond from Arg-127, and the inhibitor binds as a possible analogue of the tetrahedral transition state (or intermediate) in a promoted water pathway for peptide hydrolysis. The unidentate sulfodiimine-zinc binding mode observed in this enzyme-inhibitor complex is reminiscent of that observed in sulfonamide complexes with the zinc metalloenzyme carbonic anhydrase II, and the structural features of sulfodiimine- and sulfonamide-zinc interactions exhibit important similarities among recently determined structures of enzyme-inhibitor complexes: ionized nitrogens bind to zinc in each structure, and these nitrogens are engaged in hydrogen bond interactions with neighboring enzyme residues.

About this StructureAbout this Structure

1CPS is a Single protein structure of sequence from Bos taurus with and as ligands. Active as Carboxypeptidase A, with EC number 3.4.17.1 Full crystallographic information is available from OCA.

ReferenceReference

Structural comparison of sulfodiimine and sulfonamide inhibitors in their complexes with zinc enzymes., Cappalonga AM, Alexander RS, Christianson DW, J Biol Chem. 1992 Sep 25;267(27):19192-7. PMID:1527041

Page seeded by OCA on Thu Feb 21 12:08:27 2008

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-[[Image:1cps.jpg|left|200px]]<br /><applet load="1cps" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1cps.jpg|left|200px]]<br /><applet load="1cps" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1cps, resolution 2.25&Aring;" />
 '''STRUCTURAL COMPARISON OF SULFODIIMINE AND SULFONAMIDE INHIBITORS IN THEIR COMPLEXES WITH ZINC ENZYMES'''<br />
 ==Overview==
-The three-dimensional structure of (L(-)-2-carboxy-3-phenylpropyl), methylsulfodiimine in its complex with the zinc metalloenzyme, carboxypeptidase A has been determined at 2.25-A resolution by x-ray, crystallographic methods. This is the first example of a, sulfodiimine-containing inhibitor binding to a zinc enzyme, and the, structure of the enzyme-inhibitor complex reveals that the tetrahedral, sulfodiimine group coordinates to the active site zinc ion in unidentate, fashion. The zinc-coordinated nitrogen atom of the sulfodiimine group is, also within hydrogen bonding distance to active site base Glu-270;, presumably, the sulfodiimine is ionized and accepts a hydrogen bond from, protonated Glu-270. The other sulfodiimine nitrogen accepts a hydrogen, bond from Arg-127, and the inhibitor binds as a possible analogue of the, tetrahedral transition state (or intermediate) in a promoted water pathway, for peptide hydrolysis. The unidentate sulfodiimine-zinc binding mode, observed in this enzyme-inhibitor complex is reminiscent of that observed, in sulfonamide complexes with the zinc metalloenzyme carbonic anhydrase, II, and the structural features of sulfodiimine- and sulfonamide-zinc, interactions exhibit important similarities among recently determined, structures of enzyme-inhibitor complexes: ionized nitrogens bind to zinc, in each structure, and these nitrogens are engaged in hydrogen bond, interactions with neighboring enzyme residues.
+The three-dimensional structure of (L(-)-2-carboxy-3-phenylpropyl) methylsulfodiimine in its complex with the zinc metalloenzyme carboxypeptidase A has been determined at 2.25-A resolution by x-ray crystallographic methods. This is the first example of a sulfodiimine-containing inhibitor binding to a zinc enzyme, and the structure of the enzyme-inhibitor complex reveals that the tetrahedral sulfodiimine group coordinates to the active site zinc ion in unidentate fashion. The zinc-coordinated nitrogen atom of the sulfodiimine group is also within hydrogen bonding distance to active site base Glu-270; presumably, the sulfodiimine is ionized and accepts a hydrogen bond from protonated Glu-270. The other sulfodiimine nitrogen accepts a hydrogen bond from Arg-127, and the inhibitor binds as a possible analogue of the tetrahedral transition state (or intermediate) in a promoted water pathway for peptide hydrolysis. The unidentate sulfodiimine-zinc binding mode observed in this enzyme-inhibitor complex is reminiscent of that observed in sulfonamide complexes with the zinc metalloenzyme carbonic anhydrase II, and the structural features of sulfodiimine- and sulfonamide-zinc interactions exhibit important similarities among recently determined structures of enzyme-inhibitor complexes: ionized nitrogens bind to zinc in each structure, and these nitrogens are engaged in hydrogen bond interactions with neighboring enzyme residues.
 ==About this Structure==
-CPS is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with ZN and CPM as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Carboxypeptidase_A Carboxypeptidase A], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.17.1 3.4.17.1] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1CPS OCA].
+CPS is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with <scene name='pdbligand=ZN:'>ZN</scene> and <scene name='pdbligand=CPM:'>CPM</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Carboxypeptidase_A Carboxypeptidase A], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.17.1 3.4.17.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1CPS OCA].
 ==Reference==
@@ Line 14: / Line 14: @@
 [[Category: Carboxypeptidase A]]
 [[Category: Single protein]]
-[[Category: Alexander, R.S.]]
+[[Category: Alexander, R S.]]
-[[Category: Cappalonga, A.M.]]
+[[Category: Cappalonga, A M.]]
-[[Category: Christianson, D.W.]]
+[[Category: Christianson, D W.]]
 [[Category: CPM]]
 [[Category: ZN]]
 [[Category: hydrolase(c-terminal peptidase)]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 12:39:31 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:08:27 2008''