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Topological Specificity in Inhibitor Recognition by Proteolytic Enzymes. Jeni Lauer-Fields. Matrix Metalloproteinases. Seiki, Current Opinion Cell Biology ( 2002) 14, 624-632. MMP Structures Superimposed. Bode, Cellular Molecular Life Sci. ( 1999) 55, 639-652.

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topological specificity in inhibitor recognition by proteolytic enzymes

Topological Specificity in Inhibitor Recognition by Proteolytic Enzymes

Jeni Lauer-Fields

matrix metalloproteinases
Matrix Metalloproteinases

Seiki, Current Opinion Cell Biology ( 2002) 14, 624-632.

mmp structures superimposed
MMP Structures Superimposed

Bode, Cellular Molecular Life Sci. ( 1999) 55, 639-652.

tissue inhibitors of metalloproteinases
Tissue Inhibitors of Metalloproteinases
  • Regulate activity of MMPs
  • Form tight non-covalent 1:1 complex with MMPs
  • Regulate ECM turnover and other cellular processes
  • Two domains, with N-terminal domain retaining most of the inhibitory activity
  • Four human TIMPs (1-4), constitutive and regulated expression patterns

Abraham et al. Current Vascular Pharmacology ( 2005) 3, 369-379.

endothelin fold as a scaffold for timp based inhibitors

Endothelin-Fold as a Scaffold for TIMP-Based Inhibitors

Endothelins are 21 residue proteins with vasoactive properties

Family members; endothelins and sarafotoxins

Contain 2 disulfide bonds and moderate -helical content

Comparison with TIMP three-dimensional structure, obvious similarities

PDB file: 1SRB

determinants of mmp binding
Determinants of MMP Binding
  • ~75% of contacts are from region including residues 1-4 and residues 66-69
  • -amino and carbonyl groups of Cys1 coordinate Zn++
  • -OH of residue 2 displaces MMP-bound H2O necessary for hydrolysis

TIMP-1

Brew et al. Biochim. Biophys. Acta, 1477 (2000) 267-283.

sarafotoxin variants
Sarafotoxin Variants

H-CSCKDMTDKECLYFCHQDVIW-OH

H-CSCKDMTDKECLYFCHQD-OH

H-CSCKDMTDKECLYFCVQD-OH

H-CSCADMTDKECLYFCHQD-OH

H-CSCSDMTDKECLYFCHQD-OH

H-CSCKDMTDKECLYFCMSEMS-NH2

H-CSCSDMTDKECLYFCMSEMS-NH2

Ac-CSCSDMTDKECLYFCMSEMS-NH2

H-XSXSDMTDKEXLYFXMSEMS-NH2

Ac-XSXSDMTDKEXLYFXMSEMS-NH2

molecular docking with mmp 1
Molecular Docking with MMP-1

PDB file generated by PatchDock

current work
Current Work
  • 2D NMR Spectra for STX-S4 and STX-S4-CT
  • Make a new model based on NMR data
  • Repeat docking and analysis with NMR-based model
biomolecular proton nmr
Biomolecular Proton NMR

http://www.embl.de/nmr/sattler/lab/

biomolecular proton nmr1
Biomolecular Proton NMR

http://www.embl.de/nmr/sattler/lab/

summary
Summary
  • Endothelin-fold is a good template for peptide-based inhibitors of MMPs
  • Enhance selectivity between MMPs and other metalloproteinases (ADAM/ADAMTS)
  • Inhibition is related to endothelin-fold as well as N-terminal charge
  • Mechanism may be similar to TIMPs
acknowledgements
Acknowledgements

Biomedical Sciences

Keith Brew

Vijaya Iragavarapu Shuo Wei

Tyrone Ferns

Gina Spruill

Chemistry and Biochemistry

Gregg Fields

Frank Mari

Mare Cudic

Imperial College

Hideaki Nagase

Rob Visse