2bkl: Difference between revisions
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==Overview== | ==Overview== | ||
Prolyl endopeptidases (PEPs) are a unique class of serine proteases with, considerable therapeutic potential for the treatment of celiac sprue. The, crystal structures of two didomain PEPs have been solved in alternative, configurations, thereby providing insights into the mode of action of, these enzymes. The structure of the Sphingomonas capsulata PEP, solved and, refined to 1.8-A resolution, revealed an open configuration of the active, site. In contrast, the inhibitor-bound PEP from Myxococcus xanthus was, crystallized (1.5-A resolution) in a closed form. Comparative analysis of, the two structures highlights a critical role for the domain interface in, regulating interdomain dynamics and substrate specificity. Structure-based, mutagenesis of the M. xanthus PEP confirms an important ... | Prolyl endopeptidases (PEPs) are a unique class of serine proteases with, considerable therapeutic potential for the treatment of celiac sprue. The, crystal structures of two didomain PEPs have been solved in alternative, configurations, thereby providing insights into the mode of action of, these enzymes. The structure of the Sphingomonas capsulata PEP, solved and, refined to 1.8-A resolution, revealed an open configuration of the active, site. In contrast, the inhibitor-bound PEP from Myxococcus xanthus was, crystallized (1.5-A resolution) in a closed form. Comparative analysis of, the two structures highlights a critical role for the domain interface in, regulating interdomain dynamics and substrate specificity. Structure-based, mutagenesis of the M. xanthus PEP confirms an important role for several, interfacial residues. A salt bridge between Arg-572 and Asp-196/Glu-197, appears to act as a latch for opening or closing the didomain enzyme, and, Arg-572 and Ile-575 may also help secure the incoming peptide substrate to, the open form of the enzyme. Arg-618 and Asp-145 are responsible for, anchoring the invariant proline residue in the active site of this, postproline-cleaving enzyme. A model is proposed for the docking of a, representative substrate PQPQLPYPQPQLP in the active site, where the, N-terminal substrate residues interact extensively with the catalytic, domain, and the C-terminal residues stretch into the propeller domain., Given the promise of the M. xanthus PEP as an oral therapeutic enzyme for, treating celiac sprue, our results provide a strong foundation for further, optimization of the PEP's clinically useful features. | ||
==About this Structure== | ==About this Structure== | ||
2BKL is a | 2BKL is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Myxococcus_xanthus Myxococcus xanthus] with SO4, ZAH and MES as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Prolyl_oligopeptidase Prolyl oligopeptidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.26 3.4.21.26] Structure known Active Site: CAT. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2BKL OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: protease]] | [[Category: protease]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 15:13:16 2007'' | ||
