Summary: Tissue inhibitor of metalloproteinase
Tissue inhibitor of metalloproteinase Provide feedback
Members of this family are common in extracellular regions of vertebrate species
Williamson RA, Martorell G, Carr MD, Murphy G, Docherty AJ, Freedman RB, Feeney J; , Biochemistry 1994;33:11745-11759.: Solution structure of the active domain of tissue inhibitor of metalloproteinases-2. A new member of the OB fold protein family. PUBMED:7918391 EPMC:7918391
Internal database links
|Similarity to PfamA using HHSearch:||NTR|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR001820
Peptide proteinase inhibitors can be found as single domain proteins or as single or multiple domains within proteins; these are referred to as either simple or compound inhibitors, respectively. In many cases they are synthesised as part of a larger precursor protein, either as a prepropeptide or as an N-terminal domain associated with an inactive peptidase or zymogen. This domain prevents access of the substrate to the active site. Removal of the N-terminal inhibitor domain either by interaction with a second peptidase or by autocatalytic cleavage activates the zymogen. Other inhibitors interact direct with proteinases using a simple noncovalent lock and key mechanism; while yet others use a conformational change-based trapping mechanism that depends on their structural and thermodynamic properties.
Tissue inhibitors of metalloproteinases (TIMPs, [PUBMED:2793861, PUBMED:1850705, PUBMED:1512267]) and their target matrix metalloproteinases (MMPs, MEROPS peptidase family M10A) are important in connective tissue re-modelling in diseases of the cardiovascular system and in the physiological degradation of connective tissue, as well as in pathological states such as tumour invasion and arthritis. TIMPs belong to MEROPS proteinase inhibitor family I35, clan IT.
TIMPs complex with extracellular matrix metalloproteinases (such as collagenases) and irreversibly inactivate them. Members of this family are common in extracellular regions of vertebrate species [PUBMED:7918391]. TIMPs are proteins of about 200 amino acid residues, 12 of which are cysteines involved in disulphide bonds [PUBMED:2163605]. The basic structure of such a type of inhibitor is shown in the following schematic representation:
+-----------------------------+ +--------------+ | | | | CxCxCxxxxxxxxxxxxxxxxxCxxxxxxxxxCxxxxxxxCxCxCxCxCxxxxxCxxCxxx | | | | | | | | | +-----------------|-----------------+ +-+ +-----+ +---------------------+ 'C': conserved cysteine involved in a disulphide bond.
The crystal structure of the human proMMP-2/TIMP-2 complex reveals an interaction between the hemopexin domain of proMMP-2 and the C-terminal domain of TIMP-2, leaving the catalytic site of MMP-2 and the inhibitory site of TIMP-2 distant and spatially isolated. The interfacial contact of these two proteins is characterised by two distinct binding regions composed of alternating hydrophobic and hydrophilic interactions. This unique structure provides information for how specificity for non-inhibitory MMP/TIMP complex formation is achieved [PUBMED:12032297].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||metalloendopeptidase inhibitor activity (GO:0008191)|
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This superfamily consists of the C-terminal domains of netrins, complement proteins C3, C4, C5, secreted frizzled-related proteins, and type I procollagen C-proteinase enhancer proteins, as well as the homologous N-terminal domains of tissue inhibitors of metalloproteinases (TIMPs).
The clan contains the following 2 members:NTR TIMP
We make a range of alignments for each Pfam-A family:
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Curation and family details
|Seed source:||Pfam-B_1239 (release 3.0)|
|Number in seed:||25|
|Number in full:||416|
|Average length of the domain:||147.00 aa|
|Average identity of full alignment:||35 %|
|Average coverage of the sequence by the domain:||78.34 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||12|
|Download:||download the raw HMM for this family|
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the TIMP domain has been found. There are 18 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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