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J. Biol. Chem., Vol. 276, Issue 20, 17405-17412, May 18, 2001
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From the The individual zinc endoproteinases
of the tissue degrading matrix metalloproteinase (MMP) family share a
common catalytic architecture but are differentiated with respect to
substrate specificity, localization, and activation. Variation in
domain structure and more subtle structural differences control their characteristic specificity profiles for substrates from among four
distinct classes (Nagase, H., and Woessner, J. F. J. (1999) J. Biol. Chem. 274, 21491-21494). Exploitation of
these differences may be decisive for the design of anticancer or other
drugs, which should be highly selective for their particular MMP
targets. Based on the 1.8-Å crystal structure of human neutrophil
collagenase (MMP-8) in complex with an active site-directed inhibitor
(RO200-1770), we identify and describe new structural determinants for
substrate and inhibitor recognition in addition to the primary
substrate recognition sites. RO200-1770 induces a major rearrangement
at a position relevant to substrate recognition near the MMP-8 active site (Ala206-Asn218). In stromelysin (MMP-3),
competing stabilizing interactions at the analogous segment hinder a
similar rearrangement, consistent with kinetic profiling of several
MMPs. Despite the apparent dissimilarity of the inhibitors, the central
2-hydroxypyrimidine-4,6-dione (barbiturate) ring of the inhibitor
RO200-1770 mimics the interactions of the hydroxamate-derived inhibitor
batimastat (Grams, F., Reinemer, P., Powers, J. C., Kleine, T.,
Pieper, M., Tschesche, H., Huber, R., and Bode, W. (1995)
Eur. J. Biochem. 228, 830-841) for binding to MMP-8.
The two additional phenyl and piperidyl ring substituents of the
inhibitor bind into the S1' and S2' pockets of MMP-8, respectively. The
crystal lattice contains a hydrogen bond between the O We dedicate this work to Prof. H. Tschesche on the occasion of his 65th birthday.
The 1.8-Å Crystal Structure of a Matrix Metalloproteinase
8-Barbiturate Inhibitor Complex Reveals a Previously Unobserved
Mechanism for Collagenase Substrate Recognition*
§,
,,,,, and
Department of Structural Research, Max
Planck Institute for Biochemistry, D-82152 Martinsried, Germany,
Pharmaceutical Research, Roche Diagnostics GmbH, D-82372
Penzberg, Germany, and ¶ Molecular Design, Pharmaceuticals
Division, F. Hoffmann La Roche Ltd., CH-4070 Basel, Switzerland
group of Ser209 and N
1 of
His207 of a symmetry related molecule; this interaction
suggests a model for recognition of hydroxyprolines present in
physiological substrates. We also identify a collagenase-characteristic
cis-peptide bond, Asn188-Tyr189, on a loop
essential for collagenolytic activity. The sequence conservation
pattern at this position marks this cis-peptide bond as a determinant
for triple-helical collagen recognition and processing.
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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