Matrix metalloproteinase

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   Print3D File:3ma2a.png MT1-MMP-TIMP-1 complex Matrix metalloproteinases (MMP) are Zinc-dependent endopeptidases. MMP degrades extracellular matrix proteins. MMPs are produced by 28 different genes and are classified according to their protein substrates. 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 Metalloproteinase 12 Molecular Playground/MMP9 Molecular Playground/MMP14 Matrix metalloproteinases Metalloproteases MT1-MMP-TIMP-1 complex . MT1-MMP-TIMP-1 complex The human matrix metalloproteinases (MMPs) family comprises a large group of structurally homologous zinc-dependent endopeptidases (e.g. membrane type-1 matrix metalloproteinase (MT1-MMP) (darkmagenta) and membrane type-3 matrix metalloproteinase (MT3-MMP) (magenta), click to see structural comparison) 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, membrane type-3 matrix metalloproteinase (MT3-MMP) can form complex with wild-type TIMP-1 (1uea, colored orange). The WT-TIMP-1 binding interface (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, five main chain hydrogen bonds (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. Membrane type-1 matrix metalloproteinase (MT1-MMP) (darkmagenta) also forms complex with wild-type TIMP-1 (2j0t, colored orange), producing similar hydrogen bond network in the WT TIMP-1 binding interface as well as in the case with MT3-MMP. This network of hydrogen bonds stabilizes the CD and EF loops that compose the binding interface. Importantly, the hydrogen bond between Cys1 and Ser68 may position the amino and carboxyl groups of Cys1 to effectively coordinate the Zn2+ ion. 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, but is inhibited by the structural homologous TIMP-2 (1bqq). The single point mutation T98L (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 relatively similar. Even the structure of MT3-MMP-WT-TIMP-1 is similar to those of MT1-MMP-TIMP-1s (with wild-type and TIMP-1 T98L mutant). Leu98 is pointing toward MT1-MMP residues Pro259 and Phe260, establishing a strong hydrophobic core, which is situated near the MT1-MMP catalytic Zn2+ ion surrounded by His239, His243, and His249. 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 key hydrogen bond 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

Updated on 30-December-2014

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• MMP1 interstitial or fibroblast collagenase
  • Matrix Metalloproteinase 12 – pro-hMMP – human
    
  • Molecular Playground/MMP9 – hMMP (mutant)
    
  • Molecular Playground/MMP14, Matrix metalloproteinases - hMMP catalytic domain
    
  • Metalloproteases, MT1-MMP-TIMP-1 complex - hMMP catalytic domain + inhibitor
    
  • 1uea, 2j0t, 1bqq - hMMP catalytic domain - NMR
    
  • 3ma2 – MMP - pig
• MMP2 gelatinase-A
  • 1qib, 1ck7 - hMMP catalytic domain (mutant)
    
  • 1rtg - hMMP hemopexin-like domain
    
  • 1ks0 – hMMP first fibronectin type II domain – NMR
    
  • 1cxw - hMMP second fibronectin type II domain – NMR
    
  • 1j7m - hMMP third fibronectin type II domain (mutant) – NMR
    
  • 1gen – hMMP C terminal
    
  • 1eak – pro-hMMP catalytic domain (mutant) + peptide inhibitor
    
  • 3ayu - hMMP catalytic domain (mutant) + peptide inhibitor
    
  • 1hov, 1eub - hMMP catalytic domain + inhibitor– NMR
    
  • 1gxd – pro-hMMP (mutant) + TIMP-2
• MMP3 stromelysin 1
  • 1qia, 1qic, 1cqr, 1slm - hMMP catalytic domain
    
  • 3ohl, 3oho, 1g49, 1ciz, 1b8y, 1caq, 1usn, 2usn, 1ums, 1umt, 2d1n, 2d1o, 2ow9, 1bqo, 1g4k, 1b3d, 1biw, 1c3i, 1d5j, 1d7x, 1d8f, 1d8m, 1g05, 1hfs, 1hy7, 2srt, 4dpe, 4g9l, 4ja1 - hMMP catalytic domain + inhibitor
    
  • 1c8t - hMMP catalytic domain (mutant) + inhibitor
    
  • 1uea - hMMP catalytic domain + TIMP-1
    
  • 1oo9 - hMMP catalytic domain + TIMP-1 N terminal
    
  • 2jt5, 2jt6, 2jnp, 3usn, 1sln, 1bm6 - hMMP catalytic domain + inhibitor – NMR
    
• MMP7 matrilysin
  • 2y6c, 2y6d, 2ddy, 1mmp, 1mmq, 1mmr – hMMP catalytic domain + inhibitor
    
• MMP8 neutrophil collagenase
  • 2oy4, 1mnc - hMMP catalytic domain
    
  • 3dng, 3dpe, 3dpf, 1zp5, 1jh1, 1jj9, 1i76, 1a85, 1mmb, 1zs0, 1zvx, 1lbc – hMMP catalytic domain + inhibitor
    
  • 1i73, 2oy2, 1jan, 1jao, 1jap, 1jaq - hMMP catalytic domain + peptide inhibitor
    
  • 1a86 - hMMP catalytic domain + aspartate-based inhibitor
• MMP9 gelatinase-B
  • 1l6j - pro-hMMP
    
  • 1itv – hMMP haemopexin-like domain
    
  • 1gkc - hMMP catalytic domain + inhibitor
    
  • 2ovx, 2ovz, 2ow0, 2ow1, 2ow2, 1gkd, 4h1q, 4h82, 4hma, 4h2e, 4h3x - hMMP catalytic domain (mutant) + inhibitor
    
  • 4jij, 4jqg - hMMP catalytic domain (mutant) + FRET substrate
    
• MMP10 stromelysin 2
  • 1q3a - hMMP catalytic domain (mutant)
    
  • 3v96, 4ilw - hMMP catalytic domain + metalloproteinase inhibitor
• MMP11 stromelysin 3
  • 1hv5 - hMMP catalytic domain + inhibitor
    
• MMP12 macrophage
  • 3ba0, 2oxu - hMMP
    
  • 2krj, 2k9c - hMMP catalytic domain – NMR
    
  • 1jk3, 1jiz, 2oxu - hMMP catalytic domain
    
  • 4ijo - hMMP catalytic domain (mutant)
    
  • 2poj - hMMP catalytic domain (mutant) - NMR
    
  • 2jxy - hMMP hemopexin-like domain - NMR
    
  • 3n2u, 3n2v, 2wo8, 2wo9, 2woa, 1utt, 1utz, 1ros, 3rts, 3rtt – hMMP catalytic domain + inhibitor
    
  • 3lk8, 3lik, 3lil, 3lir, 3ljg, 3nx7, 3lka, 3ehx, 3ehy, 3f15, 3f16, 3f17, 3f18, 3f19, 3f1a, 1y93, 1rmz, 1os2, 1os9, 2hu6, 3ts4, 3tsk, 3uvc, 4gql, 4gr0, 4gr3, 4gr8, 4h30, 4h49, 4h76, 4h84, 4io3, 1jk3,4efs, 4gql, 4gr0, 4gr3, 4gr8, 4guy, 4h30, 4h49, 4h76, 4h84, 4i03 - hMMP catalytic domain (mutant) + inhibitor
    
  • 2oxn, 2oxz, 2oxw - hMMP catalytic domain (mutant) + peptide
    
  • 2k2g, 2z2d - hMMP catalytic domain + inhibitor - NMR
    
  • 2w0d, 1ycm, 1z3j - hMMP catalytic domain (mutant) + inhibitor - NMR
    
• MMP13 collagenase 3
  • 1cxv - MMP catalytic domain - mouse
    
  • 1pex – hMMP hemopexin-like domain
    
  • 2yig, 3ljz, 3kec, 3kej, 3kek, 3kry, 3i7g, 3i7i, 3elm, 2pjt, 2ozr, 1xuc, 1xud, 1xur, 1you, 1ztq, 3o2x, 3zxh, 4a7b, 1fls, 1fm1, 456c, 830c, 3tvc, 4jp4, 4jpa – hMMP catalytic domain + inhibitor
    
  • 2e2d - hMMP catalytic domain + TIMP-2
    
  • 4fu4, 4fvl, 4g0d - hMMP catalytic domain (mutant) + pro-domain peptide
    
• MMP14 Membrane T1
  • 3ma2 – hMMP residues 112-292 + TIMP-1 (mutant)
    
  • 1buv, 1bqq - hMMP + TIMP-2
    
  • 3c7x – hMMP hemopexin-like domain
• MMP16 Membrane T3
  • 1rm8 - hMMP catalytic domain + inhibitor
    
• MMP20 enamelysin
  • 2jsd - hMMP catalytic domain + inhibitor - NMR
    
• MMP23 CA-MMP
  • 2k72 – hMMP residues 254-290 - NMR
    
• MMP adamalysin
  • 1iag – MMP – diamondback rattlesnake

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Alexander Berchansky, Michal Harel