title: Evaluation of macrocyclic Grb2 SH2 domain-binding peptide mimetics prepared by ring-closing metathesis of C-terminal allylglycines with an N-terminal beta-vinyl-substituted phosphotyrosyl mimetic.
abstract: Preferential binding of ligands to Grb2 SH2 domains in beta-bend conformations has made peptide cyclization a logical means of effecting affinity enhancement. This is based on the concept that constraint of open-chain sequences to bend geometries may reduce entropy penalties of binding. The current study extends this approach by undertaking ring-closing metathesis (RCM) macrocyclization between i and i+3 residues through a process involving allylglycines and beta-vinyl-functionalized residues. Ring closure in this fashion results in minimal macrocyclic tetrapeptide mimetics. The predominant effects of such macrocyclization on Grb2 SH2 domain binding affinity were increases in rates of association (from 7- to 16-fold) relative to an open-chain congener, while decreases in dissociation rates were less pronounced (approximately 2-fold). The significant increases in association rates were consistent with pre-ordering of solution conformations to near those required for binding. Data from NMR experiments and molecular modeling simulations were used to interpret the binding results. An understanding of the conformational consequences of such i to i+3 ring closure may facilitate its application to other systems where bend geometries are desired.
authors.affiliation: Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute, National Institutes of Health, PO Box B, Bldg. 376 Boyles St. Frederick, MD 21702-1201, USA.
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.forename: Rajeshri G
authors.initials: RG
authors.lastname: Karki
authors.forename: Zhen-Dan
authors.initials: ZD
authors.lastname: Shi
authors.forename: Karen M
authors.initials: KM
authors.lastname: Worthy
authors.forename: Lakshman
authors.initials: L
authors.lastname: Bindu
authors.forename: Oleg
authors.initials: O
authors.lastname: Chertov
authors.forename: Dominic
authors.initials: D
authors.lastname: Esposito
authors.forename: Peter
authors.initials: P
authors.lastname: Frank
authors.forename: William K
authors.initials: WK
authors.lastname: Gillette
authors.forename: Melissa
authors.initials: M
authors.lastname: Maderia
authors.forename: James
authors.initials: J
authors.lastname: Hartley
authors.forename: Marc C
authors.initials: MC
authors.lastname: Nicklaus
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Barchi
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fisher
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry*; D000501:Allylglycine / Q000737:chemistry*; D003500:Cyclization; D051380:GRB2 Adaptor Protein; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D019000:Phosphotyrosine / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D047028:Macrocyclic Compounds; D010455:Peptides; D000501:Allylglycine; D019000:Phosphotyrosine