4nfe | pdb_00004nfe

Human kallikrein-related peptidase 2 in complex with benzamidine

spinqualitylabelsall models 4nfe, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4nfe is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: BEN, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function KLK2_HUMAN Glandular kallikreins cleave Met-Lys and Arg-Ser bonds in kininogen to release Lys-bradykinin. Publication Abstract from PubMed Human kallikrein-related peptidase (KLK) 2 is a tryptic serine protease predominantly expressed in prostatic tissue and secreted into prostatic fluid, a major component of seminal fluid. Most likely, it activates and complements chymotryptic KLK3 (prostate-specific antigen) in cleaving seminal clotting proteins, resulting in sperm liquefaction. KLK2 belongs to the "classical" KLKs 1-3, which share an extended 99- or kallikrein loop near their non-primed substrate binding site. Here, we report the 1.9 A crystal structures of two KLK2-small molecule inhibitor complexes. In both structures, discontinuous electron density for the 99-loop indicates that this loop is largely disordered. We provide evidence that the 99-loop is responsible for two biochemical peculiarities of KLK2, i.e. reversible inhibition by micromolar Zn2+ concentrations and permanent inactivation by autocatalytic cleavage. Indeed, several 99-loop mutants of KLK2 displayed an altered susceptibility to Zn2+, which located the Zn2+ binding site at the 99-loop/active site interface. In addition, we identified an autolysis site between residues 95e and 95f in the 99-loop, whose elimination prevented the mature enzyme from limited autolysis and irreversible inactivation. An exhaustive comparison of KLK2 with related structures revealed that in the KLK family, the 99-, 148- and 220-loop exist in open and closed conformations, allowing or preventing substrate access, which extends the concept of conformational selection in trypsin-related proteases. Taken together, our novel biochemical and structural data on KLK2 identify its 99-loop as a key player in activity regulation. Structure-Function Analyses of Human Kallikrein-Related Peptidase 2 Establish the 99-Loop as Master Regulator of Activity.,Skala W, Utzschneider DT, Magdolen V, Debela M, Guo S, Craik CS, Brandstetter H, Goettig P J Biol Chem. 2014 Oct 16. pii: jbc.M114.598201. PMID:25326387 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Kallikrein 3D structures

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