3tvj: Difference between revisions
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==Catalytic fragment of MASP-2 in complex with its specific inhibitor developed by directed evolution on SGCI scaffold== | |||
<StructureSection load='3tvj' size='340' side='right' caption='[[3tvj]], [[Resolution|resolution]] 1.28Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3tvj]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Schistocerca_gregaria Schistocerca gregaria]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TVJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3TVJ FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4djz|4djz]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MASP2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]), GenBank: Y09605.1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=7010 Schistocerca gregaria])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mannan-binding_lectin-associated_serine_protease-2 Mannan-binding lectin-associated serine protease-2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.104 3.4.21.104] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3tvj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tvj OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3tvj RCSB], [http://www.ebi.ac.uk/pdbsum/3tvj PDBsum]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[http://www.uniprot.org/uniprot/MASP2_HUMAN MASP2_HUMAN]] Defects in MASP2 are the cause of MASP2 deficiency (MASPD) [MIM:[http://omim.org/entry/613791 613791]]. MASPD is a disorder that results in autoimmune manifestations, recurrent severe infections, and chronic inflammatory disease.<ref>PMID:12904520</ref> <ref>PMID:17252003</ref> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/MASP2_HUMAN MASP2_HUMAN]] Serum protease that plays an important role in the activation of the complement system via mannose-binding lectin. After activation by auto-catalytic cleavage it cleaves C2 and C4, leading to their activation and to the formation of C3 convertase.<ref>PMID:10946292</ref> [[http://www.uniprot.org/uniprot/SGP1_SCHGR SGP1_SCHGR]] In vitro, SGPI-1/SGCI is active against alpha-chymotrypsin and trypsin while SGPI-2/SGTI is active against alpha-chymotrypsin and pancreatic elastase. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The lectin pathway is an antibody-independent activation route of the complement system. It provides immediate defense against pathogens and altered self-cells, but it also causes severe tissue damage after stroke, heart attack and other ischemia reperfusion injuries. The pathway is triggered by target-binding of pattern recognition molecules leading to the activation of zymogen mannan-binding lectin-associated serine proteases (MASPs). MASP-2 is considered as the autonomous pathway-activator while MASP-1 as an auxiliary component. We evolved a pair of monospecific MASP inhibitors. In accordance with the key role of MASP-2, the MASP-2 inhibitor completely blocks the lectin pathway activation. Importantly, the MASP-1 inhibitor does the same demonstrating that MASP-1 is not an auxiliary but an essential pathway component. We report the first Michaelis-like complex structures of MASP-1 and MASP-2 formed with substrate-like inhibitors. The 1.28 A resolution MASP-2 structure reveals significant plasticity of the protease suggesting that either an induced fit or a conformational selection mechanism should contribute to the extreme specificity of the enzyme. | |||
Monospecific inhibitors show that both mannan-binding lectin-associated serine protease (MASP)-1 and -2 are essential for lectin pathway activation and reveal structural plasticity of MASP-2.,Heja D, Harmat V, Fodor K, Wilmanns M, Dobo J, Kekesi KA, Zavodszky P, Gal P, Pal G J Biol Chem. 2012 Apr 16. PMID:22511776<ref>PMID:22511776</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Mannan-binding lectin-associated serine protease-2]] | [[Category: Mannan-binding lectin-associated serine protease-2]] | ||
[[Category: Schistocerca gregaria]] | [[Category: Schistocerca gregaria]] | ||
[[Category: Dobo, J | [[Category: Dobo, J]] | ||
[[Category: Gal, P | [[Category: Gal, P]] | ||
[[Category: Harmat, V | [[Category: Harmat, V]] | ||
[[Category: Heja, D | [[Category: Heja, D]] | ||
[[Category: Kekesi, K A | [[Category: Kekesi, K A]] | ||
[[Category: Pal, G | [[Category: Pal, G]] | ||
[[Category: Szasz, R | [[Category: Szasz, R]] | ||
[[Category: Zavodszky, P | [[Category: Zavodszky, P]] | ||
[[Category: Allostery]] | [[Category: Allostery]] | ||
[[Category: Hydrolase]] | [[Category: Hydrolase]] | ||
[[Category: In vitro evolution]] | [[Category: In vitro evolution]] | ||
[[Category: Specific inhibitor]] | [[Category: Specific inhibitor]] | ||
