4qci

Publication Abstract from PubMed

Platelet derived growth factor-BB (PDGF-BB) is an important mitogen and cell survival factor during development. PDGF-BB binds PDGF receptor-beta (PDGFRbeta) to trigger receptor dimerization and tyrosine kinase activation. We present the pharmacological and biophysical characterization of a blocking PDGF-BB monoclonal antibody, MOR8457, and contrast this to PDGFRbeta. MOR8457 binds to PDGF-BB with high affinity and selectivity, and prevents PDGF-BB induced cell proliferation competitively and with high potency. The structural characterization of the MOR8457-PDGF-BB complex indicates that MOR8457 binds with a 2:1 stoichiometry, but that binding of a single MOR8457 moiety is sufficient to prevent binding to PDGFRbeta. Comparison of the MOR8457-PDGF-BB structure with that of the PDGFRbeta-PDGF-BB complex suggested the potential reason for this was a substantial bending and twisting of PDGF-BB in the MOR8457 structure, relative to the structures of PDGF-BB alone, bound to a PDGF-BB aptamer or PDGFRbeta, which makes it nonpermissive for PDGFRbeta binding. These biochemical and structural data offer insights into the permissive structure of PDGF-BB needed for agonism as well as strategies for developing specific PDGF ligand antagonists.

Characterization of Binding Mode of Action of a Blocking Anti-Platelet-Derived Growth Factor (PDGF)-B Monoclonal Antibody, MOR8457, Reveals Conformational Flexibility and Avidity Needed for PDGF-BB To Bind PDGF Receptor-beta,Kuai J, Mosyak L, Brooks J, Cain M, Carven GJ, Ogawa S, Ishino T, Tam M, Lavallie ER, Yang Z, Ponsel D, Rauchenberger R, Arch R, Pullen N Biochemistry. 2015 Mar 6. PMID:25707433^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.