1zs0: Difference between revisions

Revision as of 17:18, 21 February 2008

Crystal structure of the complex between MMP-8 and a phosphonate inhibitor (S-enantiomer)

OverviewOverview

Potent and selective inhibitors of matrix metalloproteinases (MMPs), a family of zinc proteases that can degrade all the components of the extracellular matrix, could be useful for treatment of diseases such as cancer and arthritis. The most potent MMP inhibitors are based on hydroxamate as zinc-binding group (ZBG). alpha-Arylsulfonylamino phosphonates incorporate a particularly favorable combination of phosphonate as ZBG and arylsulfonylamino backbone so that their affinity exceptionally attains the nanomolar strength frequently observed for hydroxamate analogues. The detailed mode of binding of [1-(4'-methoxybiphenyl-4-sulfonylamino)-2-methylpropyl]phosphonate has been clarified by the crystal structures of the complexes that the R- and S-enantiomers respectively form with MMP-8. The reasons for the preferential MMP-8 inhibition by the R-phosphonate are underlined and the differences in the mode of binding of analogous alpha-arylsulfonylamino hydroxamates and carboxylates are discussed.

About this StructureAbout this Structure

1ZS0 is a Single protein structure of sequence from Homo sapiens with , , and as ligands. Active as Neutrophil collagenase, with EC number 3.4.24.34 Full crystallographic information is available from OCA.

ReferenceReference

Structural insight into the stereoselective inhibition of MMP-8 by enantiomeric sulfonamide phosphonates., Pochetti G, Gavuzzo E, Campestre C, Agamennone M, Tortorella P, Consalvi V, Gallina C, Hiller O, Tschesche H, Tucker PA, Mazza F, J Med Chem. 2006 Feb 9;49(3):923-31. PMID:16451058

Page seeded by OCA on Thu Feb 21 16:18:32 2008

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OCA

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-[[Image:1zs0.gif|left|200px]]<br />
+[[Image:1zs0.gif|left|200px]]<br /><applet load="1zs0" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="1zs0" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="1zs0, resolution 1.56&Aring;" />
 '''Crystal structure of the complex between MMP-8 and a phosphonate inhibitor (S-enantiomer)'''<br />
 ==Overview==
-Potent and selective inhibitors of matrix metalloproteinases (MMPs), a, family of zinc proteases that can degrade all the components of the, extracellular matrix, could be useful for treatment of diseases such as, cancer and arthritis. The most potent MMP inhibitors are based on, hydroxamate as zinc-binding group (ZBG). alpha-Arylsulfonylamino, phosphonates incorporate a particularly favorable combination of, phosphonate as ZBG and arylsulfonylamino backbone so that their affinity, exceptionally attains the nanomolar strength frequently observed for, hydroxamate analogues. The detailed mode of binding of, [1-(4'-methoxybiphenyl-4-sulfonylamino)-2-methylpropyl]phosphonate has, been clarified by the crystal structures of the complexes that the R- and, S-enantiomers respectively form with MMP-8. The reasons for the, preferential MMP-8 inhibition by the R-phosphonate are underlined and the, differences in the mode of binding of analogous alpha-arylsulfonylamino, hydroxamates and carboxylates are discussed.
+Potent and selective inhibitors of matrix metalloproteinases (MMPs), a family of zinc proteases that can degrade all the components of the extracellular matrix, could be useful for treatment of diseases such as cancer and arthritis. The most potent MMP inhibitors are based on hydroxamate as zinc-binding group (ZBG). alpha-Arylsulfonylamino phosphonates incorporate a particularly favorable combination of phosphonate as ZBG and arylsulfonylamino backbone so that their affinity exceptionally attains the nanomolar strength frequently observed for hydroxamate analogues. The detailed mode of binding of [1-(4'-methoxybiphenyl-4-sulfonylamino)-2-methylpropyl]phosphonate has been clarified by the crystal structures of the complexes that the R- and S-enantiomers respectively form with MMP-8. The reasons for the preferential MMP-8 inhibition by the R-phosphonate are underlined and the differences in the mode of binding of analogous alpha-arylsulfonylamino hydroxamates and carboxylates are discussed.
 ==About this Structure==
-ZS0 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with CA, ZN, EIN and MES as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Neutrophil_collagenase Neutrophil collagenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.34 3.4.24.34] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1ZS0 OCA].
+ZS0 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=CA:'>CA</scene>, <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=EIN:'>EIN</scene> and <scene name='pdbligand=MES:'>MES</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Neutrophil_collagenase Neutrophil collagenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.34 3.4.24.34] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ZS0 OCA].
 ==Reference==
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 [[Category: Tortorella, P.]]
 [[Category: Tschesche, H.]]
-[[Category: Tucker, P.A.]]
+[[Category: Tucker, P A.]]
 [[Category: CA]]
 [[Category: EIN]]
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 [[Category: sulphonamide junction]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 20:39:59 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:18:32 2008''