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[[Image:1su3.png|left|200px|thumb|Crystal Structure of Human pro MMP1 complex, [[1su3]]]]
<StructureSection load='M1.pdb' size='350' side='right' scene='MT1-MMP-TIMP-1_complex/Cv2/8' caption='Complex of MMP14 (magenta) and TIMP-1 (orange) with Ca+2 (green) and Zn+2 (grey) ions (PDB code [[3ma2]])'>
{{STRUCTURE_1su3|  PDB=1su3  | SIZE=400| SCENE=Matrix_metalloproteinase/Cv/1 |right|  CAPTION= Human pro MMP1 complex with HEPES, sulfate, Ca+2, Cl-1, Na+1, Zn+2 ions, [[1su3]] }}


__TOC__
== 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<ref>PMID:10419448</ref>. See details in<br />


* [[Matrix metalloproteinases]]<br />
* [[Metalloproteases]]<br />
* [[MT1-MMP-TIMP-1 complex]]<br />.


MMPs are produced by 28 different genes and are classified according to their protein substrates.<br />
* '''MMP1''' cleaves collagens I, II, III, VII and X.<br />
* '''MMP2''' cleaves collagen IV and denatured collagen.<br />
* '''MMP3''' cleaves the core protein of aggrecan and plasminogen activator.<br />
* '''MMP7''' cleaves proteoglycans, fibronectin, elastin and casein.<br />
* '''MMP8''' cleaves aggrecan.<br />
* '''MMP9''' cleaves gelatin.  See details in [[Molecular Playground/MMP9]]<br />
* '''MMP10''' cleaves collagens III, IV, V, fibronectin,gelatin and aggrecan.<br />
* '''MMP11''' cleaves peptides in human tumors.<br />
* '''MMP12''' cleaves collagens I and III. See details in [[Matrix Metalloproteinase 12]] <br />
* '''MMP13''' cleaves collagen II and laminin-5 γ2.<br />
* '''MMP14''' is a membrane-type MMP which cleaves aggrecan.  See details in [[Molecular Playground/MMP14]]<br />
* '''MMP16''' cleaves collagen III, proteoglycans, fibronectin, gelatin, vitronectin, laminin and α2-macroglobulin.<br />
* '''MMP20''' cleaves E-cadherin.<br />
* '''MMP23''' function is unknown.<br />
* '''MMP adamalysin''' is a snake toxin.  See details in [[Atragin]]<br />


== Relevance ==
MMPs have a role in cancer progression<ref>PMID:21087457</ref>.  MMP-2 and MMP-9 secretion is elevated in ovarian cancer and are associated with poor prognosis<ref>PMID:19360311</ref>.  MMP-8, MMP-9, MMP-13 and MMP-14 have a role in periodontal diseases<ref>PMID:8315570</ref>.


'''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. The images at the left and at the right correspond to one representative MMP, ''i.e.'' the crystal structure of human pro MMP1 ([[1su3]]).  See details of MMP12 in [[Matrix Metalloproteinase 12]].  More details of MMP in
* [[Matrix metalloproteinases]]
* [[Metalloproteases]]
* [[MT1-MMP-TIMP-1 complex]].
{{TOC limit|limit=2}}
{{Clear}}   
{{Clear}}   


==MT1-MMP-TIMP-1 complex==
==MT1-MMP-TIMP-1 complex==
<StructureSection load='M1.pdb' size='500' side='right' scene='MT1-MMP-TIMP-1_complex/Cv2/8' caption=''>


The human matrix metalloproteinases (MMPs) family comprises a large group of structurally homologous zinc-dependent endopeptidases (''e.g.'' <scene name='MT1-MMP-TIMP-1_complex/Cv2/9'>membrane type-1 matrix metalloproteinase (MT1-MMP)</scene> <font color='darkmagenta'><b>(darkmagenta)</b></font> and <scene name='MT1-MMP-TIMP-1_complex/Cv/14'>membrane type-3 matrix metalloproteinase (MT3-MMP)</scene> <font color='magenta'><b>(magenta)</b></font>, <scene name='MT1-MMP-TIMP-1_complex/Cv2/10'>click to see structural comparison</scene>) 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, <scene name='MT1-MMP-TIMP-1_complex/Cv/14'>membrane type-3 matrix metalloproteinase (MT3-MMP)</scene> can form complex with <scene name='MT1-MMP-TIMP-1_complex/Cv/12'>wild-type TIMP-1</scene> ([[1uea]], <font color='orange'><b>colored orange</b></font>). <scene name='MT1-MMP-TIMP-1_complex/Cv/13'>The WT-TIMP-1 binding interface</scene> <font color='cyan'><b>(cyan)</b></font> 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 <font color='red'><b>red sticks</b></font>. In general, <scene name='MT1-MMP-TIMP-1_complex/Cv1/2'>five main chain hydrogen bonds</scene> (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.
The human matrix metalloproteinases (MMPs) family comprises a large group of structurally homologous zinc-dependent endopeptidases (''e.g.'' <scene name='MT1-MMP-TIMP-1_complex/Cv2/9'>membrane type-1 matrix metalloproteinase (MT1-MMP)</scene> <font color='darkmagenta'><b>(darkmagenta)</b></font> and <scene name='MT1-MMP-TIMP-1_complex/Cv/14'>membrane type-3 matrix metalloproteinase (MT3-MMP)</scene> <font color='magenta'><b>(magenta)</b></font>, <scene name='MT1-MMP-TIMP-1_complex/Cv2/10'>click to see structural comparison</scene>) 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, <scene name='MT1-MMP-TIMP-1_complex/Cv/14'>membrane type-3 matrix metalloproteinase (MT3-MMP)</scene> can form complex with <scene name='MT1-MMP-TIMP-1_complex/Cv/12'>wild-type TIMP-1</scene> ([[1uea]], <font color='orange'><b>colored orange</b></font>). <scene name='MT1-MMP-TIMP-1_complex/Cv/13'>The WT-TIMP-1 binding interface</scene> <font color='cyan'><b>(cyan)</b></font> 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 <font color='red'><b>red sticks</b></font>. In general, <scene name='MT1-MMP-TIMP-1_complex/Cv1/2'>five main chain hydrogen bonds</scene> (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.
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account for the entire binding effect between MT1-MMP and TIMP-1. Statistical analysis of the <scene name='MT1-MMP-TIMP-1_complex/Cv2/15'>key hydrogen bond</scene> 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
account for the entire binding effect between MT1-MMP and TIMP-1. Statistical analysis of the <scene name='MT1-MMP-TIMP-1_complex/Cv2/15'>key hydrogen bond</scene> 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 <ref name="Grossman">PMID:20545310</ref>.   
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 <ref name="Grossman">PMID:20545310</ref>.   
 


==3D structures of matrix metalloproteinase==
[[Matrix metalloproteinase 3D structures]]


</StructureSection>
</StructureSection>
==3D structures of matrix metalloproteinase==
''Updated June 2012''
===MMP1 interstitial or fibroblast collagenase===
[[1su3]] – pro-hMMP – human<br />
[[2clt]] – hMMP (mutant)<br />
[[3shi]], [[1hfc]] - hMMP catalytic domain<br />
[[2tcl]], [[966c]] - hMMP catalytic domain + inhibitor<br />
[[2ayk]], [[3ayk]], [[4ayk]] - hMMP catalytic domain - NMR<br />
[[1fbl]] – MMP - pig
===MMP2 gelatinase-A===
[[1qib]], [[1ck7]] - hMMP catalytic domain (mutant) <BR />
[[1rtg]] - hMMP hemopexin-like domain<BR />
[[1ks0]] – hMMP first fibronectin type II domain – NMR<BR />
[[1cxw]] - hMMP second fibronectin type II domain – NMR<BR />
[[1j7m]] - hMMP third fibronectin type II domain (mutant) – NMR<BR />
[[1gen]] – hMMP C terminal <br />
[[1eak]] – pro-hMMP catalytic domain (mutant) + peptide inhibitor<br />
[[3ayu]] - hMMP catalytic domain (mutant) + peptide inhibitor<br />
[[1hov]], [[1eub]] - hMMP catalytic domain + inhibitor– NMR<BR />
[[1gxd]] – pro-hMMP (mutant) + TIMP-2
===MMP3 stromelysin 1===
[[1qia]], [[1qic]], [[1cqr]], [[1slm]] - hMMP catalytic domain<BR />
[[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]]- hMMP catalytic domain + inhibitor<br />
[[1c8t]] - hMMP catalytic domain (mutant) + inhibitor<br />
[[1uea]] - hMMP catalytic domain + TIMP-1<BR />
[[1oo9]] - hMMP catalytic domain + TIMP-1 N terminal<BR />
[[2jt5]], [[2jt6]], [[2jnp]], [[3usn]], [[1sln]], [[1bm6]] - hMMP catalytic domain + inhibitor – NMR<BR />
===MMP7 matrilysin===
[[2y6c]], [[2y6d]], [[2ddy]], [[1mmp]], [[1mmq]], [[1mmr]] – hMMP catalytic domain + inhibitor<br />
===MMP8 neutrophil collagenase===
[[2oy4]], [[1mnc]] - hMMP catalytic domain<br />
[[3dng]], [[3dpe]], [[3dpf]], [[1zp5]], [[1jh1]], [[1jj9]], [[1i76]], [[1a85]], [[1mmb]], [[1zs0]], [[1zvx]], [[1lbc]] – hMMP catalytic domain + inhibitor<br />
[[1i73]], [[2oy2]], [[1jan]], [[1jao]], [[1jap]], [[1jaq]] - hMMP catalytic domain + peptide inhibitor<br />
[[1a86]] - hMMP catalytic domain + aspartate-based inhibitor
===MMP9 gelatinase-B===
[[1l6j]] - pro-hMMP<BR />
[[1itv]] – hMMP haemopexin-like domain<br />
[[1gkc]] - hMMP catalytic domain + inhibitor<br />
[[2ovx]], [[2ovz]], [[2ow0]], [[2ow1]], [[2ow2]], [[1gkd]] - hMMP catalytic domain (mutant) + inhibitor<br />
===MMP10 stromelysin 2===
[[1q3a]] - hMMP catalytic domain (mutant)<br />
[[3v96]] - hMMP catalytic domain + metalloproteinase inhibitor
===MMP11 stromelysin 3===
[[1hv5]] - hMMP catalytic domain + inhibitor<br />
===MMP12 macrophage===
[[3ba0]], [[2oxu]] - hMMP<BR />
[[2krj]], [[2k9c]] - hMMP catalytic domain – NMR<BR />
[[1jk3]], [[1jiz]], [[2oxu]] -  hMMP catalytic domain <BR />
[[2poj]] - hMMP catalytic domain (mutant) - NMR<BR />
[[2jxy]] - hMMP hemopexin-like domain - NMR<BR />
[[3n2u]], [[3n2v]], [[2wo8]], [[2wo9]], [[2woa]], [[1utt]], [[1utz]], [[1ros]] – hMMP catalytic domain + inhibitor<br />
[[3lk8]], [[3lik]], [[3lil]], [[3lir]], [[3ljg]], [[3nx7]], [[3lka]], [[3ehx]], [[3ehy]], [[3f15]], [[3f16]], [[3f17]], [[3f18]], [[3f19]], [[3f1a]], [[1y93]], [[1rmz]], [[1os2]], [[1os9]], [[2hu6]] - hMMP catalytic domain (mutant) + inhibitor<br />
[[2oxn]], [[2oxz]], [[2oxw]] - hMMP catalytic domain (mutant) + peptide<br />
[[2k2g]], [[2z2d]] - hMMP catalytic domain + inhibitor - NMR<BR />
[[2w0d]], [[1ycm]], [[1z3j]] - hMMP catalytic domain (mutant) + inhibitor - NMR<BR />
===MMP13 collagenase 3===
[[1cxv]] - MMP catalytic domain - mouse<BR />
[[1pex]] – hMMP hemopexin-like domain<br />
[[2yig]], [[3ljz]], [[3kec]], [[3kej]], [[3kek]], [[3kry]], [[3i7g]], [[3i7i]], [[3elm]], [[2pjt]], [[2ozr]], [[1xuc]], [[1xud]], [[1xur]], [[1you]], [[1ztq]], [[3o2x]], [[3zxh]], [[4a7b]], [[1fls]], [[1fm1]], [[456c]], [[830c]] – hMMP catalytic domain + inhibitor<br />
[[2e2d]] - hMMP catalytic domain + TIMP-2
===MMP14 Membrane T1===
[[3ma2]] – hMMP residues 112-292 + TIMP-1 (mutant) <BR />
[[1buv]], [[1bqq]] - hMMP + TIMP-2<BR />
[[3c7x]] – hMMP hemopexin-like domain
===MMP16 Membrane T3===
[[1rm8]] - hMMP catalytic domain + inhibitor<br />
===MMP20 enamelysin===
[[2jsd]] - hMMP catalytic domain + inhibitor - NMR<BR />
===MMP23 CA-MMP===
[[2k72]] – hMMP residues 254-290 - NMR<BR />
===MMP adamalysin===
[[1iag]] – MMP – diamondback rattlesnake


==References==
==References==

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Michal Harel, Alexander Berchansky
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