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 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) A for the backbone atoms, 0.80(+/-0.09) A for all atoms, and 0.47(+/-0.04) A for all atoms excluding disordered side-chains. The overall structure of MMP-13 is composed of a beta-sheet consisting of five beta-strands in a mixed parallel and anti-parallel arrangement and three alpha-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 A 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.
Moy
F J
FJ
Department of Biological Chemistry, Wyeth Research, 85 Bolton St., Cambridge, MA 02140, USA.
Chanda
P K
PK
Chen
J M
JM
Cosmi
S
S
Edris
W
W
Levin
J I
JI
Powers
R
R
D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D017364:Collagenases / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D020781:Matrix Metalloproteinase 1 / Q000737:chemistry / Q000378:metabolism; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D011719:Pyrazines; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012996:Solutions; D013449:Sulfonamides; D015032:Zinc / Q000378:metabolism
C097658:CGS 27023A; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D010446:Peptide Fragments; D011480:Protease Inhibitors; D011719:Pyrazines; D012996:Solutions; D013449:Sulfonamides; C414371:WAY 151693; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020781:Matrix Metalloproteinase 1; D015032:Zinc