4AUO

Crystal structure of MMP-1(E200A) in complex with a triple-helical collagen peptide

Summary for 4AUO

• Entry DOI: 10.2210/pdb4auo/pdb
• Related: 1AYK 1CGE 1CGF 1CGL 1HFC 1SU3 2AYK 2CLT 2J0T 2TCL 3AYK 4AYK 966C
• Descriptor: INTERSTITIAL COLLAGENASE, TRIPLE-HELICAL COLLAGEN PEPTIDE, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: hydrolase-peptide complex, hydrolase/peptide
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Secreted, extracellular space, extracellular matrix (Probable): P03956
• Total number of polymer chains: 8
• Total formula weight: 107741.06

Authors

Manka, S.W.,Carafoli, F.,Visse, R.,Bihan, D.,Raynal, N.,Farndale, R.W.,Murphy, G.,Enghild, J.J.,Hohenester, E.,Nagase, H. (deposition date: 2012-05-18, release date: 2012-07-11, Last modification date: 2023-12-20)

Primary citation

Manka, S.W.,Carafoli, F.,Visse, R.,Bihan, D.,Raynal, N.,Farndale, R.W.,Murphy, G.,Enghild, J.J.,Hohenester, E.,Nagase, H.
Structural Insights Into Triple-Helical Collagen Cleavage by Matrix Metalloproteinase 1
Proc.Natl.Acad.Sci.USA, 109:12461-, 2012

PubMed Abstract: Collagenases of the matrix metalloproteinase (MMP) family play major roles in morphogenesis, tissue repair, and human diseases, but how they recognize and cleave the collagen triple helix is not fully understood. Here, we report temperature-dependent binding of a catalytically inactive MMP-1 mutant (E200A) to collagen through the cooperative action of its catalytic and hemopexin domains. Contact between the two molecules was mapped by screening the Collagen Toolkit peptide library and by hydrogen/deuterium exchange. The crystal structure of MMP-1(E200A) bound to a triple-helical collagen peptide revealed extensive interactions of the 115-Å-long triple helix with both MMP-1 domains. An exosite in the hemopexin domain, which binds the leucine 10 residues C-terminal to the scissile bond, is critical for collagenolysis and represents a unique target for inhibitor development. The scissile bond is not correctly positioned for hydrolysis in the crystallized complex. A productive binding mode is readily modeled, without altering the MMP-1 structure or the exosite interactions, by axial rotation of the collagen homotrimer. Interdomain flexing of the enzyme and a localized excursion of the collagen chain closest to the active site, facilitated by thermal loosening of the substrate, may lead to the first transition state of collagenolysis.

PubMed: 22761315
DOI: 10.1073/PNAS.1204991109

Experimental method

X-RAY DIFFRACTION (3 Å)