High-resolution solution structure of the catalytic fragment of human collagenase-3 (MMP-13) complexed with a hydroxamic acid inhibitor

Franklin J. Moy, Pranab K. Chanda, James M. Chen, Scott Cosmi, Wade Edris, Jeremy I. Levin, Robert Powers

Research output: Contribution to journalArticle

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Abstract

The high-resolution solution structure of the catalytic fragment of human collagenase-3 (MMP-13) complexed with a sulfonamide derivative of a hydroxamic acid compound (WAY-151693) has been determined by multidimensional heteronuclear NMR. A total of 30 structures were calculated for residues 7-164 by means of hybrid distance geometry-simulated annealing using a total of 3280 experimental NMR restraints. The atomic rms distribution about the mean coordinate positions for the 30 structures is 0.43(±0.05) Å for the backbone atoms, 0.80(±0.09) Å for all atoms, and 0.47(±0.04) Å for all atoms excluding disordered side-chains. The overall structure of MMP-13 is composed of a β-sheet consisting of five β-strands in a mixed parallel and anti-parallel arrangement and three α-helices where its overall fold is consistent with previously solved MMP structures. A comparison of the NMR structure of MMP-13 with the published 1.6 Å resolution X-ray structure indicates that the major differences between the structures is associated with loop dynamics and crystal-packing interactions. The side-chains of some active-site residues for the NMR and X-ray structures of MMP-13 adopt distinct conformations. This is attributed to the presence of unique inhibitors in the two structures that encounter distinct interactions with MMP-13. The major structural difference observed between the MMP-13 and MMP-1 NMR structures is the relative size and shape of the S1' pocket where this pocket is significantly longer for MMP-13, nearly reaching the surface of the protein. Additionally, MMP-1 and MMP-13 exhibit different dynamic properties for the active-site loop and the structural Zn-binding region. The inhibitor WAY-151693 is well defined in the MMP-13 active-site based on a total of 52 distance restraints. The binding motif of WAY-151693 in the MMP-13 complex is consistent with our previously reported MMP-1:CGS-27023A NMR structure and is similar to the MMP-13: RS-130830 X-ray structure. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)671-689
Number of pages19
JournalJournal of Molecular Biology
Volume302
Issue number3
DOIs
StatePublished - Sep 22 2000

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Matrix Metalloproteinase 13
Hydroxamic Acids
Matrix Metalloproteinases
Catalytic Domain
X-Rays
Biomolecular Nuclear Magnetic Resonance
Sulfonamides

Keywords

  • Human collagenase-3
  • Hydroxamic acid
  • Matrix metalloproteinase
  • NMR
  • Solution structure

ASJC Scopus subject areas

  • Molecular Biology

Cite this

High-resolution solution structure of the catalytic fragment of human collagenase-3 (MMP-13) complexed with a hydroxamic acid inhibitor. / Moy, Franklin J.; Chanda, Pranab K.; Chen, James M.; Cosmi, Scott; Edris, Wade; Levin, Jeremy I.; Powers, Robert.

In: Journal of Molecular Biology, Vol. 302, No. 3, 22.09.2000, p. 671-689.

Research output: Contribution to journalArticle

Moy, Franklin J. ; Chanda, Pranab K. ; Chen, James M. ; Cosmi, Scott ; Edris, Wade ; Levin, Jeremy I. ; Powers, Robert. / High-resolution solution structure of the catalytic fragment of human collagenase-3 (MMP-13) complexed with a hydroxamic acid inhibitor. In: Journal of Molecular Biology. 2000 ; Vol. 302, No. 3. pp. 671-689.
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AU - Cosmi, Scott

AU - Edris, Wade

AU - Levin, Jeremy I.

AU - Powers, Robert

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N2 - The high-resolution solution structure of the catalytic fragment of human collagenase-3 (MMP-13) complexed with a sulfonamide derivative of a hydroxamic acid compound (WAY-151693) has been determined by multidimensional heteronuclear NMR. A total of 30 structures were calculated for residues 7-164 by means of hybrid distance geometry-simulated annealing using a total of 3280 experimental NMR restraints. The atomic rms distribution about the mean coordinate positions for the 30 structures is 0.43(±0.05) Å for the backbone atoms, 0.80(±0.09) Å for all atoms, and 0.47(±0.04) Å for all atoms excluding disordered side-chains. The overall structure of MMP-13 is composed of a β-sheet consisting of five β-strands in a mixed parallel and anti-parallel arrangement and three α-helices where its overall fold is consistent with previously solved MMP structures. A comparison of the NMR structure of MMP-13 with the published 1.6 Å resolution X-ray structure indicates that the major differences between the structures is associated with loop dynamics and crystal-packing interactions. The side-chains of some active-site residues for the NMR and X-ray structures of MMP-13 adopt distinct conformations. This is attributed to the presence of unique inhibitors in the two structures that encounter distinct interactions with MMP-13. The major structural difference observed between the MMP-13 and MMP-1 NMR structures is the relative size and shape of the S1' pocket where this pocket is significantly longer for MMP-13, nearly reaching the surface of the protein. Additionally, MMP-1 and MMP-13 exhibit different dynamic properties for the active-site loop and the structural Zn-binding region. The inhibitor WAY-151693 is well defined in the MMP-13 active-site based on a total of 52 distance restraints. The binding motif of WAY-151693 in the MMP-13 complex is consistent with our previously reported MMP-1:CGS-27023A NMR structure and is similar to the MMP-13: RS-130830 X-ray structure. (C) 2000 Academic Press.

AB - The high-resolution solution structure of the catalytic fragment of human collagenase-3 (MMP-13) complexed with a sulfonamide derivative of a hydroxamic acid compound (WAY-151693) has been determined by multidimensional heteronuclear NMR. A total of 30 structures were calculated for residues 7-164 by means of hybrid distance geometry-simulated annealing using a total of 3280 experimental NMR restraints. The atomic rms distribution about the mean coordinate positions for the 30 structures is 0.43(±0.05) Å for the backbone atoms, 0.80(±0.09) Å for all atoms, and 0.47(±0.04) Å for all atoms excluding disordered side-chains. The overall structure of MMP-13 is composed of a β-sheet consisting of five β-strands in a mixed parallel and anti-parallel arrangement and three α-helices where its overall fold is consistent with previously solved MMP structures. A comparison of the NMR structure of MMP-13 with the published 1.6 Å resolution X-ray structure indicates that the major differences between the structures is associated with loop dynamics and crystal-packing interactions. The side-chains of some active-site residues for the NMR and X-ray structures of MMP-13 adopt distinct conformations. This is attributed to the presence of unique inhibitors in the two structures that encounter distinct interactions with MMP-13. The major structural difference observed between the MMP-13 and MMP-1 NMR structures is the relative size and shape of the S1' pocket where this pocket is significantly longer for MMP-13, nearly reaching the surface of the protein. Additionally, MMP-1 and MMP-13 exhibit different dynamic properties for the active-site loop and the structural Zn-binding region. The inhibitor WAY-151693 is well defined in the MMP-13 active-site based on a total of 52 distance restraints. The binding motif of WAY-151693 in the MMP-13 complex is consistent with our previously reported MMP-1:CGS-27023A NMR structure and is similar to the MMP-13: RS-130830 X-ray structure. (C) 2000 Academic Press.

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