1bhf: Difference between revisions
New page: left|200px<br /> <applet load="1bhf" size="450" color="white" frame="true" align="right" spinBox="true" caption="1bhf, resolution 1.8Å" /> '''P56LCK SH2 DOMAIN IN... |
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[[Image:1bhf.gif|left|200px]]<br /> | [[Image:1bhf.gif|left|200px]]<br /><applet load="1bhf" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="1bhf, resolution 1.8Å" /> | caption="1bhf, resolution 1.8Å" /> | ||
'''P56LCK SH2 DOMAIN INHIBITOR COMPLEX'''<br /> | '''P56LCK SH2 DOMAIN INHIBITOR COMPLEX'''<br /> | ||
==Overview== | ==Overview== | ||
The crystal structure of human p56(lck) SH2 domain in complex with an | The crystal structure of human p56(lck) SH2 domain in complex with an inhibitor containing the singly charged p-(carboxymethyl)phenylalanine residue (cmF) as a phosphotyrosine (Tyr(P) or pY) replacement has been determined at 1.8 A resolution. The binding mode of the acetyl-cmF-Glu-Glu-Ile (cmFEEI) inhibitor is very similar to that of the pYEEI inhibitor, confirming that the cmFEEI inhibitor has a similar mechanism of SH2 domain inhibition despite its significantly reduced potency. Observed conformational differences in the side chain of the cmF residue can be interpreted in terms of maintaining similar interactions with the SH2 domain as the Tyr(P) residue. The crystal structure of the free p56(lck) SH2 domain has been determined at 1.9 A resolution and shows an open conformation for the BC loop and an open phosphotyrosine binding pocket, in contrast to earlier studies on the src SH2 domain that showed mostly closed conformation. The structural information presented here suggests that the carboxymethyl-phenylalanine residue may be a viable Tyr(P) replacement and represents an attractive starting point for the design and development of SH2 domain inhibitors with better pharmaceutical profiles. | ||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
1BHF is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ACE as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] Full crystallographic information is available from [http:// | 1BHF is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ACE:'>ACE</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1BHF OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Jakes, S.]] | [[Category: Jakes, S.]] | ||
[[Category: Lukas, S.]] | [[Category: Lukas, S.]] | ||
[[Category: Proudfoot, J | [[Category: Proudfoot, J R.]] | ||
[[Category: Schembri-King, J.]] | [[Category: Schembri-King, J.]] | ||
[[Category: Tong, L.]] | [[Category: Tong, L.]] | ||
[[Category: Warren, T | [[Category: Warren, T C.]] | ||
[[Category: ACE]] | [[Category: ACE]] | ||
[[Category: complex (sh2 domain/inhibitor)]] | [[Category: complex (sh2 domain/inhibitor)]] | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 11:55:18 2008'' | ||
Revision as of 12:55, 21 February 2008
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P56LCK SH2 DOMAIN INHIBITOR COMPLEX
OverviewOverview
The crystal structure of human p56(lck) SH2 domain in complex with an inhibitor containing the singly charged p-(carboxymethyl)phenylalanine residue (cmF) as a phosphotyrosine (Tyr(P) or pY) replacement has been determined at 1.8 A resolution. The binding mode of the acetyl-cmF-Glu-Glu-Ile (cmFEEI) inhibitor is very similar to that of the pYEEI inhibitor, confirming that the cmFEEI inhibitor has a similar mechanism of SH2 domain inhibition despite its significantly reduced potency. Observed conformational differences in the side chain of the cmF residue can be interpreted in terms of maintaining similar interactions with the SH2 domain as the Tyr(P) residue. The crystal structure of the free p56(lck) SH2 domain has been determined at 1.9 A resolution and shows an open conformation for the BC loop and an open phosphotyrosine binding pocket, in contrast to earlier studies on the src SH2 domain that showed mostly closed conformation. The structural information presented here suggests that the carboxymethyl-phenylalanine residue may be a viable Tyr(P) replacement and represents an attractive starting point for the design and development of SH2 domain inhibitors with better pharmaceutical profiles.
DiseaseDisease
Known disease associated with this structure: SCID due to LCK deficiency OMIM:[153390]
About this StructureAbout this Structure
1BHF is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2 Full crystallographic information is available from OCA.
ReferenceReference
Carboxymethyl-phenylalanine as a replacement for phosphotyrosine in SH2 domain binding., Tong L, Warren TC, Lukas S, Schembri-King J, Betageri R, Proudfoot JR, Jakes S, J Biol Chem. 1998 Aug 7;273(32):20238-42. PMID:9685372
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