Hydrophobic D-amino acids in the design of peptide ligands for the pp60src SH2 domain.
Src homology-2 (SH2) domains, containing approximately 100 amino acid residues, are noncatalytic motifs involved with intracellular signal transduction. These domains can be found on nonreceptor kinases, phosphatases, and in regulatory adapter proteins among others. SH2 domains bind proteins containing phosphotyrosine (pTyr) residues in a sequence specific manner. Our efforts have focused on designing peptide mimetic ligands for the SH2 domain of the nonreceptor tyrosine kinase pp60src. We employed the cocrystal structure of the 11mer Glu-Pro-Gln-pTyr-Glu-Glu-Ile-Pro-IIe-Tyr-Leu IC50 = 800 nM as a starting point for our design efforts. These efforts have resulted in the discovery of tripeptide ligands containing D-amino acids that are only 2-fold less potent than the 11mer.
Plummer
M S
MS
Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48106, USA.
Lunney
E A
EA
Para
K S
KS
Prasad
J V
JV
Shahripour
A
A
Singh
J
J
Stankovic
C J
CJ
Humblet
C
C
Fergus
J H
JH
Marks
J S
JS
Sawyer
T K
TK
D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D015195:Drug Design; D007457:Iodine Radioisotopes; D007553:Isotope Labeling; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000737:chemistry* / Q000378:metabolism; D011869:Radioligand Assay; D013329:Structure-Activity Relationship; D018909:src Homology Domains
D007457:Iodine Radioisotopes; D008024:Ligands; D009842:Oligopeptides; D016392:Proto-Oncogene Proteins pp60(c-src)