1BHF

P56LCK SH2 DOMAIN INHIBITOR COMPLEX

Summary for 1BHF

• Entry DOI: 10.2210/pdb1bhf/pdb
• Related PRD ID: PRD_000406
• Descriptor: T-LYMPHOCYTE-SPECIFIC PROTEIN TYROSINE KINASE P56LCK, INHIBITOR ACE-IPA-GLU-GLU-ILE (3 entities in total)
• Functional Keywords: sh2 domain, phosphorylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P06239
• Total number of polymer chains: 2
• Total formula weight: 12878.28

Authors

Tong, L.,Warren, T.C.,Lukas, S.,Schembri-King, J.,Betageri, R.,Proudfoot, J.R.,Jakes, S. (deposition date: 1998-06-08, release date: 1998-10-21, Last modification date: 2024-11-13)

Primary citation

Tong, L.,Warren, T.C.,Lukas, S.,Schembri-King, J.,Betageri, R.,Proudfoot, J.R.,Jakes, S.
Carboxymethyl-phenylalanine as a replacement for phosphotyrosine in SH2 domain binding.
J.Biol.Chem., 273:20238-20242, 1998

PubMed Abstract: 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.

PubMed: 9685372
DOI: 10.1074/jbc.273.32.20238

Experimental method

X-RAY DIFFRACTION (1.8 Å)