Christopher M Read

Publications (2)14.68 Total impact

• Article: The interface between catalytic and hemopexin domains in matrix metalloproteinase-1 conceals a collagen binding exosite.

  Laurence H Arnold, Louise E Butt, Stephen H Prior, Christopher M Read, Gregg B Fields, Andrew R Pickford
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  ABSTRACT: Matrix metalloproteinase-1 (MMP-1) is an instigator of collagenolysis, the catabolism of triple helical collagen. Previous studies have implicated its hemopexin (HPX) domain in binding and possibly destabilizing the collagen substrate in preparation for hydrolysis of the polypeptide backbone by the catalytic (CAT) domain. Here, we use biophysical methods to study the complex formed between the MMP-1 HPX domain and a synthetic triple helical peptide (THP) that encompasses the MMP-1 cleavage site of the collagen α1(I) chain. The two components interact with 1:1 stoichiometry and micromolar affinity via a binding site within blades 1 and 2 of the four-bladed HPX domain propeller. Subsequent site-directed mutagenesis and assay implicates blade 1 residues Phe(301), Val(319), and Asp(338) in collagen binding. Intriguingly, Phe(301) is partially masked by the CAT domain in the crystal structure of full-length MMP-1 implying that transient separation of the domains is important in collagen recognition. However, mutation of this residue in the intact enzyme disrupts the CAT-HPX interface resulting in a drastic decrease in binding activity. Thus, a balanced equilibrium between these compact and dislocated states may be an essential feature of MMP-1 collagenase activity.
  Journal of Biological Chemistry 12/2011; 286(52):45073-82. · 4.77 Impact Factor
• Article: Design and structure of stapled peptides binding to estrogen receptors.

  Chris Phillips, Lee R Roberts, Markus Schade, Richard Bazin, Andrew Bent, Nichola L Davies, Rob Moore, Andrew D Pannifer, Andrew R Pickford, Stephen H Prior, Christopher M Read, Andrew Scott, David G Brown, Bin Xu, Stephen L Irving
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  ABSTRACT: Synthetic peptides that specifically bind nuclear hormone receptors offer an alternative approach to small molecules for the modulation of receptor signaling and subsequent gene expression. Here we describe the design of a series of novel stapled peptides that bind the coactivator peptide site of estrogen receptors. Using a number of biophysical techniques, including crystal structure analysis of receptor-stapled peptide complexes, we describe in detail the molecular interactions and demonstrate that all-hydrocarbon staples modulate molecular recognition events. The findings have implications for the design of stapled peptides in general.
  Journal of the American Chemical Society 06/2011; 133(25):9696-9. · 9.91 Impact Factor