1LKK

HUMAN P56-LCK TYROSINE KINASE SH2 DOMAIN IN COMPLEX WITH THE PHOSPHOTYROSYL PEPTIDE AC-PTYR-GLU-GLU-ILE (PYEEI PEPTIDE)

Summary for 1LKK

• Entry DOI: 10.2210/pdb1lkk/pdb
• Descriptor: HUMAN P56 TYROSINE KINASE, PHOSPHOTYROSYL PEPTIDE AC-PTYR-GLU-GLU-ILE, ACETYL GROUP, ... (4 entities in total)
• Functional Keywords: complex (tyrosine kinase-peptide), complex (tyrosine kinase-peptide) complex, complex (tyrosine kinase/peptide)
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: P06239
• Total number of polymer chains: 2
• Total formula weight: 12688.01

Authors

Tong, L. (deposition date: 1995-11-10, release date: 1996-03-08, Last modification date: 2024-08-07)

Primary citation

Tong, L.,Warren, T.C.,King, J.,Betageri, R.,Rose, J.,Jakes, S.
Crystal structures of the human p56lck SH2 domain in complex with two short phosphotyrosyl peptides at 1.0 A and 1.8 A resolution.
J.Mol.Biol., 256:601-610, 1996

PubMed Abstract: src homology 2 (SH2) domains are modules of about 100 amino acid residues and bind to phosphotyrosine-containing motifs in a sequence-specific manner. They play important roles in intracellular signal transduction and represent potential targets for pharmacological intervention. The protein tyrosine kinase p56lck is a member of the src family and is involved in T-cell activation. The crystal structure of its SH2 domain with an 11-residue peptide showed that the phosphotyrosine and the Ile residue at the pY + 3 position are recognized by the SH2 domain. We present here the crystal structure of the SH2 domain of human p56lck in complex with the short phosphotyrosyl peptide Ac-pTyr-Glu-Glu-Ile (pYEEI peptide) at 1.0 A resolution. The structural analysis at atomic resolution reveals that residue Arg134 (alphaA2), which interacts with the phosphotyrosine side-chain, is present in two conformations in the complex. The structure at 1.8 A resolution of the complex with the phosphotyrosyl peptide Ac-pTyr-Glu-Glu-Gly (pYEEG peptide), which is 11 fold less potent, shows another binding mode for the pY + 3 residue as well as rearrangements of the side-chain of Arg196 (EF3) and one of the water molecules at the base of the pY + 3 pocket. The structure of the complex with the short pYEEI peptide at atomic resolution represents a good starting point for the design and optimization of new inhibitors. Comparative structural analysis of many different inhibitor complexes will be an important component of this drug discovery process.

PubMed: 8604142
DOI: 10.1006/jmbi.1996.0112

Experimental method

X-RAY DIFFRACTION (1 Å)