4qci | pdb_00004qci
PDGF-B blocking antibody bound to PDGF-BB
Structural highlights
Disease[PDGFB_HUMAN] Note=A chromosomal aberration involving PDGFB is found in dermatofibrosarcoma protuberans. Translocation t(17;22)(q22;q13) with PDGFB.[1] Function[PDGFB_HUMAN] Growth factor that plays an essential role in the regulation of embryonic development, cell proliferation, cell migration, survival and chemotaxis. Potent mitogen for cells of mesenchymal origin. Required for normal proliferation and recruitment of pericytes and vascular smooth muscle cells in the central nervous system, skin, lung, heart and placenta. Required for normal blood vessel development, and for normal development of kidney glomeruli. Plays an important role in wound healing. Signaling is modulated by the formation of heterodimers with PDGFA (By similarity). Publication Abstract from PubMedPlatelet 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. References
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