1jh1

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[[Image:1jh1.jpg|left|200px]]<br /><applet load="1jh1" size="350" color="white" frame="true" align="right" spinBox="true"
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[[Image:1jh1.jpg|left|200px]]
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caption="1jh1, resolution 2.7&Aring;" />
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'''Crystal Structure of MMP-8 complexed with a 6H-1,3,4-thiadiazine derived inhibitor'''<br />
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{{Structure
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|PDB= 1jh1 |SIZE=350|CAPTION= <scene name='initialview01'>1jh1</scene>, resolution 2.7&Aring;
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|SITE=
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|LIGAND= <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene> and <scene name='pdbligand=JST:BUT-3-ENYL-[5-(4-CHLORO-PHENYL)-3,6-DIHYDRO-[1,3,4]THIADIAZIN-2-YLIDENE]-AMINE'>JST</scene>
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|ACTIVITY= [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]
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|GENE= MMP-8 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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}}
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'''Crystal Structure of MMP-8 complexed with a 6H-1,3,4-thiadiazine derived inhibitor'''
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==Overview==
==Overview==
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==About this Structure==
==About this Structure==
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1JH1 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> and <scene name='pdbligand=JST:'>JST</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=1JH1 OCA].
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1JH1 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1JH1 OCA].
==Reference==
==Reference==
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Structure-based design and synthesis of potent matrix metalloproteinase inhibitors derived from a 6H-1,3,4-thiadiazine scaffold., Schroder J, Henke A, Wenzel H, Brandstetter H, Stammler HG, Stammler A, Pfeiffer WD, Tschesche H, J Med Chem. 2001 Sep 27;44(20):3231-43. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11563922 11563922]
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Structure-based design and synthesis of potent matrix metalloproteinase inhibitors derived from a 6H-1,3,4-thiadiazine scaffold., Schroder J, Henke A, Wenzel H, Brandstetter H, Stammler HG, Stammler A, Pfeiffer WD, Tschesche H, J Med Chem. 2001 Sep 27;44(20):3231-43. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/11563922 11563922]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Neutrophil collagenase]]
[[Category: Neutrophil collagenase]]
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[[Category: thiadiazine]]
[[Category: thiadiazine]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:22:34 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 12:03:17 2008''

Revision as of 10:03, 20 March 2008

Image:1jh1.jpg


PDB ID 1jh1

Drag the structure with the mouse to rotate
, resolution 2.7Å
Ligands: , and
Gene: MMP-8 (Homo sapiens)
Activity: Neutrophil collagenase, with EC number 3.4.24.34
Coordinates: save as pdb, mmCIF, xml



Crystal Structure of MMP-8 complexed with a 6H-1,3,4-thiadiazine derived inhibitor


Overview

We describe a new generation of heterocyclic nonpeptide matrix metalloproteinase (MMP) inhibitors derived from a 6H-1,3,4-thiadiazine scaffold. A screening effort was utilized to identify some chiral 6-methyl-1,3,4-thiadiazines that are weak inhibitors of the catalytic domain of human neutrophil collagenase (cdMMP-8). Further optimization of the lead compounds revealed general design principles that involve the placement of a phenyl or thienyl group at position 5 of the thiadiazine ring, to improve unprimed side affinity; the incorporation of an amino group at position 2 of the thiadiazine ring as the chelating agent for the catalytic zinc; the placement of a N-sulfonamide-substituted amino acid residue at the amino group, to improve primed side affinity; and the attachment of diverse functional groups at position 4 or 5 of the phenyl or thienyl group at the unprimed side, to improve selectivity. The new compounds were assayed against eight different matrix metalloproteinases, MMP-1, cdMMP-2, cdMMP-8, MMP-9, cdMMP-12, cdMMP-13, cdMMP-14, and the ectodomain of MMP-14, respectively. A unique combination of the above-described modifications produced the selective inhibitor (2R)-N-[5-(4-bromophenyl)-6H-1,3,4-thiadiazin-2-yl]-2-[(phenylsulfonyl)ami no]propanamide with high affinity for MMP-9 (K(i) = 40 nM). X-ray crystallographic data obtained for cdMMP-8 cocrystallized with N-allyl-5-(4-chlorophenyl)-6H-1,3,4-thiadiazin-2-amine hydrobromide gave detailed design information on binding interactions for thiadiazine-based MMP inhibitors.

About this Structure

1JH1 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Structure-based design and synthesis of potent matrix metalloproteinase inhibitors derived from a 6H-1,3,4-thiadiazine scaffold., Schroder J, Henke A, Wenzel H, Brandstetter H, Stammler HG, Stammler A, Pfeiffer WD, Tschesche H, J Med Chem. 2001 Sep 27;44(20):3231-43. PMID:11563922

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