Structure-based design of peptidomimetic antagonists of p56(lck) SH2 domain.
Starting from the tetrapeptide Ac-pYEEI-NHMe and using a structure-based approach, we have designed and synthesised a peptidomimetic ligand for p56(lck) SH2 domain containing a conformationally restricted replacement for the two glutamate residues. We have explored replacments for the isoleucine residue in the pY+3 pocket and thus identified 1-(R)-amino-3-(S)-indaneacetic acid as the most potent replacement. We also report the X-ray crystal structures of two of the antagonists.
Hobbs
Christopher J
CJ
Roche Products Limited, 40 Broadwater Road, Welwyn Garden City, AL7 3AY, Hertfordshire, UK. chobbs@ionixpharma.com
Bit
Rino A
RA
Cansfield
Andrew D
AD
Harris
Bill
B
Hill
Christopher H
CH
Hilyard
Katherine L
KL
Kilford
Ian R
IR
Kitas
Eric
E
Kroehn
Antonin
A
Lovell
Peter
P
Pole
David
D
Rugman
Paul
P
Sherborne
Brad S
BS
Smith
Ian E D
IE
Vesey
David R
DR
Walmsley
D Lee
DL
Whittaker
David
D
Williams
Glyn
G
Wilson
Fiona
F
Banner
David
D
Surgenor
Allan
A
Borkakoti
Neera
N
D000818:Animals; D006224:Cricetinae; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D018698:Glutamic Acid; D008024:Ligands; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D018909:src Homology Domains
D004791:Enzyme Inhibitors; D008024:Ligands; D009842:Oligopeptides; D018698:Glutamic Acid; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)