1n7t
From Proteopedia
(New page: 200px<br /> <applet load="1n7t" size="450" color="white" frame="true" align="right" spinBox="true" caption="1n7t" /> '''ERBIN PDZ domain bound to a phage-derived p...) |
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'''ERBIN PDZ domain bound to a phage-derived peptide'''<br /> | '''ERBIN PDZ domain bound to a phage-derived peptide'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The LAP (leucine-rich repeat and PDZ-containing) family of proteins play a | + | The LAP (leucine-rich repeat and PDZ-containing) family of proteins play a role in maintaining epithelial and neuronal cell size, and mutation of these proteins can have oncogenic consequences. The LAP protein Erbin has been implicated previously in a number of cellular activities by virtue of its PDZ domain-dependent association with the C termini of both ERB-B2 and the p120-catenins. The present work describes the NMR structure of Erbin PDZ in complex with a high affinity peptide ligand and includes a comprehensive energetic analysis of both the ligand and PDZ domain side chains responsible for binding. C-terminal phage display has been used to identify preferred ligands, whereas binding affinity measurements provide precise details of the energetic importance of each ligand side chain to binding. Alanine and homolog scanning mutagenesis (in a combinatorial phage display format) identifies Erbin side chains that make energetically important contacts with the ligand. The structure of a phage-optimized peptide (Ac-TGW(-4)ETW(-1)V; IC(50) = approximately 0.15 microm) in complex with Erbin PDZ provides a structural context to understand the binding energetics. In particular, the very favorable interactions with Trp(-1) are not Erbin side chain-mediated (and therefore may be generally applicable to many PDZ domains), whereas the beta2-beta3 loop provides a binding site for the Trp(-4) side chain (specific to Erbin because it has an unusually long loop). These results contribute to a growing appreciation for the importance of at least five ligand C-terminal side chains in determining PDZ domain binding energy and highlight the mechanisms of ligand discrimination among the several hundred PDZ domains present in the human genome. |
==About this Structure== | ==About this Structure== | ||
| - | 1N7T is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http:// | + | 1N7T is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1N7T OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Koehler, M | + | [[Category: Koehler, M F.T.]] |
| - | [[Category: Lasky, L | + | [[Category: Lasky, L A.]] |
| - | [[Category: Pisabarro, M | + | [[Category: Pisabarro, M T.]] |
| - | [[Category: Sidhu, S | + | [[Category: Sidhu, S S.]] |
| - | [[Category: Skelton, N | + | [[Category: Skelton, N J.]] |
| - | [[Category: Wong, W | + | [[Category: Wong, W L.]] |
[[Category: Yeh, S.]] | [[Category: Yeh, S.]] | ||
| - | [[Category: Yin, J | + | [[Category: Yin, J P.]] |
[[Category: Zobel, K.]] | [[Category: Zobel, K.]] | ||
[[Category: c-terminal peptide complex]] | [[Category: c-terminal peptide complex]] | ||
| Line 27: | Line 26: | ||
[[Category: pdz domain]] | [[Category: pdz domain]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:03:09 2008'' |
Revision as of 12:03, 21 February 2008
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ERBIN PDZ domain bound to a phage-derived peptide
Overview
The LAP (leucine-rich repeat and PDZ-containing) family of proteins play a role in maintaining epithelial and neuronal cell size, and mutation of these proteins can have oncogenic consequences. The LAP protein Erbin has been implicated previously in a number of cellular activities by virtue of its PDZ domain-dependent association with the C termini of both ERB-B2 and the p120-catenins. The present work describes the NMR structure of Erbin PDZ in complex with a high affinity peptide ligand and includes a comprehensive energetic analysis of both the ligand and PDZ domain side chains responsible for binding. C-terminal phage display has been used to identify preferred ligands, whereas binding affinity measurements provide precise details of the energetic importance of each ligand side chain to binding. Alanine and homolog scanning mutagenesis (in a combinatorial phage display format) identifies Erbin side chains that make energetically important contacts with the ligand. The structure of a phage-optimized peptide (Ac-TGW(-4)ETW(-1)V; IC(50) = approximately 0.15 microm) in complex with Erbin PDZ provides a structural context to understand the binding energetics. In particular, the very favorable interactions with Trp(-1) are not Erbin side chain-mediated (and therefore may be generally applicable to many PDZ domains), whereas the beta2-beta3 loop provides a binding site for the Trp(-4) side chain (specific to Erbin because it has an unusually long loop). These results contribute to a growing appreciation for the importance of at least five ligand C-terminal side chains in determining PDZ domain binding energy and highlight the mechanisms of ligand discrimination among the several hundred PDZ domains present in the human genome.
About this Structure
1N7T is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Origins of PDZ domain ligand specificity. Structure determination and mutagenesis of the Erbin PDZ domain., Skelton NJ, Koehler MF, Zobel K, Wong WL, Yeh S, Pisabarro MT, Yin JP, Lasky LA, Sidhu SS, J Biol Chem. 2003 Feb 28;278(9):7645-54. Epub 2002 Nov 20. PMID:12446668
Page seeded by OCA on Thu Feb 21 14:03:09 2008
