4QCI

PDGF-B blocking antibody bound to PDGF-BB

Summary for 4QCI

• Entry DOI: 10.2210/pdb4qci/pdb
• Descriptor: anti-PDGF-BB antibody - Light Chain, anti-PDGF-BB antibody - Heavy chain, Platelet-derived growth factor subunit B, ... (4 entities in total)
• Functional Keywords: growth factor cytokine fold, growth factor hormone, pdgfr-beta receptor, extracellular, cytokine-cytokine receptor complex, cytokine/cytokine receptor
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P01127
• Total number of polymer chains: 6
• Total formula weight: 117415.94

Authors

Kuai, J.,Mosyak, L.,Tam, M.,LaVallie, E.,Pullen, N.,Carven, G. (deposition date: 2014-05-12, release date: 2015-03-11, Last modification date: 2024-10-30)

Primary citation

Kuai, J.,Mosyak, L.,Brooks, J.,Cain, M.,Carven, G.J.,Ogawa, S.,Ishino, T.,Tam, M.,Lavallie, E.R.,Yang, Z.,Ponsel, D.,Rauchenberger, R.,Arch, R.,Pullen, N.
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.
Biochemistry, 54:1918-1929, 2015

PubMed Abstract: 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.

PubMed: 25707433
DOI: 10.1021/bi5015425

Experimental method

X-RAY DIFFRACTION (2.3 Å)