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

The high-resolution solution structure of the catalytic fragment of human c ollagenase-3 (MMP-13) complexed with a sulfonamide derivative of a hydroxam ic acid compound (WAY-151693) has been determined by multidimensional heter onuclear NMR. A total of 30 structures were calculated for residues 7-164 b y means of hybrid distance geometry-simulated annealing using a total of 32 80 experimental NMR restraints. The atomic rms distribution about the mean coordinate positions for the 30 structures is 0.43(+/-0.56) Angstrom for th e backbone atoms, 0.80(+/-0.09) Angstrom for all atoms, and 0.47(+/-0.04) A for all atoms excluding disordered side-chains. The overall structure of M MP-13 is composed of a beta-sheet consisting of five beta-strands in a mixe d parallel and anti-parallel arrangement and three alpha-helices where its overall fold is consistent with previously solved MMP structures. A compari son of the NMR structure of MMP-13 with the published 1.6 Angstrom resoluti on X-ray structure indicates that the major differences between the structu res is associated with loop dynamics and crystal-packing interactions. The side-chains of some active-site residues for the NMR and X-ray structures o f MMP-13 adopt distinct conformations. This is attributed to the presence o f unique inhibitors in the two structures that encounter distinct interacti ons with MMP-13. The major structural difference observed between the MMP-1 3 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 dy namic properties for the active-site loop and the structural Zn-binding reg ion. The inhibitor WAY-151693 is well defined in the MMP-13 active-site bas ed on a total. of 52 distance restraints. The binding motif of WAY-151693 i n the MMP-13 complex is consistent with our previously reported MMP-1:CGS27 023A NMR structure and is similar to the MMP-13: RS-130830 X-ray structure. (C) 2000 Academic Press.