1yr2

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{{STRUCTURE_1yr2| PDB=1yr2 | SCENE= }}
{{STRUCTURE_1yr2| PDB=1yr2 | SCENE= }}
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'''Structural and Mechanistic Analysis of Two Prolyl Endopeptidases: Role of Inter-Domain Dynamics in Catalysis and Specificity'''
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===Structural and Mechanistic Analysis of Two Prolyl Endopeptidases: Role of Inter-Domain Dynamics in Catalysis and Specificity===
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==Overview==
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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.
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The line below this paragraph, {{ABSTRACT_PUBMED_15738423}}, adds the Publication Abstract to the page
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(as it appears on PubMed at http://www.pubmed.gov), where 15738423 is the PubMed ID number.
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{{ABSTRACT_PUBMED_15738423}}
==About this Structure==
==About this Structure==
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==Reference==
==Reference==
Structural and mechanistic analysis of two prolyl endopeptidases: role of interdomain dynamics in catalysis and specificity., Shan L, Mathews II, Khosla C, Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3599-604. Epub 2005 Feb 28. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15738423 15738423]
Structural and mechanistic analysis of two prolyl endopeptidases: role of interdomain dynamics in catalysis and specificity., Shan L, Mathews II, Khosla C, Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3599-604. Epub 2005 Feb 28. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15738423 15738423]
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Comparative biochemical analysis of three bacterial prolyl endopeptidases: implications for coeliac sprue., Shan L, Marti T, Sollid LM, Gray GM, Khosla C, Biochem J. 2004 Oct 15;383(Pt 2):311-8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15245330 15245330]
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The prolyl oligopeptidase family., Polgar L, Cell Mol Life Sci. 2002 Feb;59(2):349-62. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/11915948 11915948]
[[Category: Novosphingobium capsulatum]]
[[Category: Novosphingobium capsulatum]]
[[Category: Prolyl oligopeptidase]]
[[Category: Prolyl oligopeptidase]]
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[[Category: Mechanistic study]]
[[Category: Mechanistic study]]
[[Category: Prolyl endopeptidase]]
[[Category: Prolyl endopeptidase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 16:40:32 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 13:49:39 2008''

Revision as of 10:49, 29 July 2008

Image:1yr2.png

Template:STRUCTURE 1yr2

Structural and Mechanistic Analysis of Two Prolyl Endopeptidases: Role of Inter-Domain Dynamics in Catalysis and Specificity

Template:ABSTRACT PUBMED 15738423

About this Structure

1YR2 is a Single protein structure of sequence from Novosphingobium capsulatum. Full crystallographic information is available from OCA.

Reference

Structural and mechanistic analysis of two prolyl endopeptidases: role of interdomain dynamics in catalysis and specificity., Shan L, Mathews II, Khosla C, Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3599-604. Epub 2005 Feb 28. PMID:15738423

Comparative biochemical analysis of three bacterial prolyl endopeptidases: implications for coeliac sprue., Shan L, Marti T, Sollid LM, Gray GM, Khosla C, Biochem J. 2004 Oct 15;383(Pt 2):311-8. PMID:15245330

The prolyl oligopeptidase family., Polgar L, Cell Mol Life Sci. 2002 Feb;59(2):349-62. PMID:11915948

Page seeded by OCA on Tue Jul 29 13:49:39 2008

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