6p3q

<table><tr><td colspan='2'>[[6p3q]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6P3Q OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6P3Q FirstGlance]. <br>

</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=6p3q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p3q OCA], [http://pdbe.org/6p3q PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6p3q RCSB], [http://www.ebi.ac.uk/pdbsum/6p3q PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6p3q ProSAT]</span></td></tr>

[[http://www.uniprot.org/uniprot/CAN5_HUMAN CAN5_HUMAN]] Autosomal dominant neovascular inflammatory vitreoretinopathy. The disease is caused by mutations affecting the gene represented in this entry.

[[http://www.uniprot.org/uniprot/CAN5_HUMAN CAN5_HUMAN]] Calcium-regulated non-lysosomal thiol-protease.

Increased calpain activity is linked to neuroinflammation including a heritable retinal disease caused by hyper-activating mutations in the calcium-activated calpain-5 (CAPN5) protease. Although structures for classical calpains are known, the structure of CAPN5, a non-classical calpain, remains undetermined. Here we report the 2.8 A crystal structure of the human CAPN5 protease core (CAPN5-PC). Compared to classical calpains, CAPN5-PC requires high calcium concentrations for maximal activity. Structure-based phylogenetic analysis and multiple sequence alignment reveal that CAPN5-PC contains three elongated flexible loops compared to its classical counterparts. The presence of a disease-causing mutation (c.799G&gt;A, p.Gly267Ser) on the unique PC2L2 loop reveals a function in this region for regulating enzymatic activity. This mechanism could be transferred to distant calpains, using synthetic calpain hybrids, suggesting an evolutionary mechanism for fine-tuning calpain function by modifying flexible loops. Further, the open (inactive) conformation of CAPN5-PC provides structural insight into CAPN5-specific residues that can guide inhibitor design.

 

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== References ==

[[Category: Khan, S]]

[[Category: Koster, H J]]

[[Category: Lokesh, G]]

[[Category: Mahajan, V]]

[[Category: Sun, Y J]]

[[Category: Velez, G]]

[[Category: Yang, J]]

[[Category: Protease domain]]