1 research outputs found
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‑β
Platelet
derived growth factor-BB (PDGF-BB) is an important mitogen
and cell survival factor during development. PDGF-BB binds PDGF receptor-β
(PDGFRβ) 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 PDGFRβ. 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 PDGFRβ. Comparison of the MOR8457-PDGF-BB structure with
that of the PDGFRβ-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 PDGFRβ, which makes it nonpermissive
for PDGFRβ 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