Matrix metalloproteinase

Function Matrix metalloproteinases (MMP) are Zinc-dependent endopeptidases. MMP degrades extracellular matrix proteins. They are inhibited by proteases called tissue inhibitors of metalloproteinase (TIMP). The pro-MMP contains a pro-peptide which must be removed to render the MMP active. See details in Matrix metalloproteinases Metalloproteases MT1-MMP-TIMP-1 complex . MMPs are produced by 28 different genes and are classified according to their protein substrates. MMP1 cleaves collagens I, II, III, VII and X. MMP2 cleaves collagen IV and denatured collagen. MMP3 cleaves the core protein of aggrecan and plasminogen activator. MMP7 cleaves proteoglycans, fibronectin, elastin and casein. MMP8 cleaves aggrecan. MMP9 cleaves gelatin. See details in Molecular Playground/MMP9 MMP10 cleaves collagens III, IV, V, fibronectin,gelatin and aggrecan. MMP11 cleaves peptides in human tumors. MMP12 cleaves collagens I and III. See details in Matrix Metalloproteinase 12 MMP13 cleaves collagen II and laminin-5 γ2. MMP14 is a membrane-type MMP which cleaves aggrecan. See details in Molecular Playground/MMP14 MMP16 cleaves collagen III, proteoglycans, fibronectin, gelatin, vitronectin, laminin and α2-macroglobulin. MMP20 cleaves E-cadherin. MMP23 function is unknown. MMP adamalysin is a snake toxin. See details in Atragin Relevance MMPs have a role in cancer progression. MMP-2 and MMP-9 secretion is elevated in ovarian cancer and are associated with poor prognosis. MMP-8, MMP-9, MMP-13 and MMP-14 have a role in periodontal diseases. MT1-MMP-TIMP-1 complex The human matrix metalloproteinases (MMPs) family comprises a large group of structurally homologous zinc-dependent endopeptidases (e.g. (darkmagenta) and (magenta), ) that perform a wide variety of biological roles. In general, the MMPs are inhibited unselectively by all four known tissue inhibitors of metalloproteinases (TIMPs 1-4) which have 40-50% sequence identity. For example, can form complex with (1uea, colored orange). (cyan) is mainly composed of the N-terminal segment that approaches the active site, the AB loop (Thr33-Tyr35), the CD loop (Ala65-Cys70), and the EF loop (Thr97-Ser100). The pivotal residue, threonine 98 (Thr98), is shown as red sticks. In general, (Cys1-Ser68, Val69-Met66, Gly71-Met66, Cys70-Glu67, and Cys70-Thr98) are intimately involved in the conformational stability of TIMP binding interface when bound to MMP. (darkmagenta) also forms complex with (2j0t, colored orange), producing as well as . This network of hydrogen bonds stabilizes the CD and EF loops that compose the binding interface. Importantly, the . However, this MT1-MMP-WT-TIMP-1 complex is not tight-binding. MT1-MMP is unique since even though it exhibits high structural homology to all MMPs, it is not inhibited by TIMP-1, (1bqq). (mutant TIMP-1 is colored in yellow with T98L shown in red) transformed TIMP-1 into a high affinity inhibitor of MT1-MMP (3ma2). WT-TIMP-1, WT-TIMP-2, and TIMP-1 T98L mutant have kinetic dissociation binding constant (KD) 1.53 x 10-6, 5.61 x 10-8, and 8.70 x 10-8, respectively. So, KD of WT-TIMP-2 is 2 orders of magnitude smaller than that of WT-TIMP-1, indicating the weak affinity between MT1-MMP and WT-TIMP-1. The TIMP-1 T98L mutant regained high-affinity binding to MT1-MMP, resulting in a 2 order of magnitude decrease in KD, similar to the case for WT-TIMP-2, the in vivo inhibitor of MT1-MMP. The overall structures of the complexes of MT1-MMP-WT-TIMP-1 and MT1-MMP-mutant-T98L-TIMP-1 are . Even the structure of MT3-MMP-WT-TIMP-1 is (with wild-type and TIMP-1 T98L mutant). , which is situated near the MT1-MMP . So, this T98L replacement may stabilize the entire area by establishing a strong hydrophobic core upon binding to the enzyme. However, it seems unlikely that these additional bonds could account for the entire binding effect between MT1-MMP and TIMP-1. Statistical analysis of the stabilities in the TIMP-1 T98L mutant reveals that the hydrogen bonds network in mutant form is significantly more stable than that in WT-TIMP-1. Mutations that enhance hydrogen bond stability contribute to the stability of the bound-like, less flexible, conformation of TIMP-1, which eventually results in increasing binding affinity for MT1-MMP. Thus, mutation affected the instrinsic dynamics of the inhibitor rather than its structure, thereby facilitating the interaction . 3D structures of matrix metalloproteinase Matrix metalloproteinase 3D structures

spinqualitylabelsall models Complex of MMP14 (magenta) and TIMP-1 (orange) with Ca+2 (green) and Zn+2 (grey) ions (PDB code 3ma2) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image