title: Solution structure and backbone dynamics of the catalytic domain of matrix metalloproteinase-2 complexed with a hydroxamic acid inhibitor.
abstract: MMP-2 is a member of the matrix metalloproteinase family that has been implicated in tumor cell metastasis and angiogenesis. Here, we describe the solution structure of a catalytic domain of MMP-2 complexed with a hydroxamic acid inhibitor (SC-74020), determined by three-dimensional heteronuclear NMR spectroscopy. The catalytic domain, designated MMP-2C, has a short peptide linker replacing the internal fibronectin-domain insertion and is enzymatically active. Distance geometry-simulated annealing calculations yielded 14 converged structures with atomic root-mean-square deviations (r.m.s.d.) of 1.02 and 1.62 A from the mean coordinate positions for the backbone and for all heavy atoms, respectively, when 11 residues at the N-terminus are excluded. The structure has the same global fold as observed for other MMP catalytic domains and is similar to previously solved crystal structures of MMP-2. Differences observed between the solution and the crystal structures, near the bottom of the S1' specificity loop, appear to be induced by the large inhibitor present in the solution structure. The MMP-2C solution structure is compared with MMP-8 crystal structure bound to the same inhibitor to highlight the differences especially in the S1' specificity loop. The finding provides a structural explanation for the selectivity between MMP-2 and MMP-8 that is achieved by large inhibitors.
authors.affiliation: Discovery Research, Pharmacia Corporation, 700 Chesterfield Parkway North, St. Louis, MO 63017, USA. yiqing.g.feng@pharmacia.com
authors.forename: Yiqing
authors.initials: Y
authors.lastname: Feng
authors.forename: John J
authors.initials: JJ
authors.lastname: Likos
authors.forename: Leiming
authors.initials: L
authors.lastname: Zhu
authors.forename: Harold
authors.initials: H
authors.lastname: Woodward
authors.forename: Grace
authors.initials: G
authors.lastname: Munie
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: McDonald
authors.forename: Anna M
authors.initials: AM
authors.lastname: Stevens
authors.forename: Carol P
authors.initials: CP
authors.lastname: Howard
authors.forename: Gary A
authors.initials: GA
authors.lastname: De Crescenzo
authors.forename: Dean
authors.initials: D
authors.lastname: Welsch
authors.forename: Huey Sheng
authors.initials: HS
authors.lastname: Shieh
authors.forename: William C
authors.initials: WC
authors.lastname: Stallings
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D006877:Hydroxamic Acids; D011480:Protease Inhibitors; C466235:SC 74020; D013449:Sulfonamides; D020778:Matrix Metalloproteinase 2