Five PDGF B amino acid substitutions convert PDGF A to a PDGF B-like transforming molecule.

LaRochelle, William J.; Pierce, Jacalyn H.; May-Siroff, M; Giese, N A; Aaronson, S A

doi:10.1016/s0021-9258(18)41894-7

Cited by 42 publications

(7 citation statements)

References 28 publications

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“…The two polypeptide chains are arranged in an antiparallel manner, placing all three loops on each end of the 2-fold symmetrical dimer (Oefner et al, 1992). Epitope mapping and mutagenesis studies have indicated that the amino acid residues near or at the solvent-accessible loops are involved in receptor binding (Giese et al, 1990;Clements et al, 1991;O ¨stman et al, 1991;LaRochelle et al, 1992;Maher et al, 1993). Consistent with this notion is our observation that the binding of DNA ligands to the PDGF B-chain occurs in close proximity of loop III (phenylalanine 84) and that this binding prevents the interaction of PDGF-BB with PDGF Rand β-receptors.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory DNA Ligands to Platelet-Derived Growth Factor B-Chain

et al. 1996

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We have identified a group of DNA molecules that bind to platelet-derived growth factor (PDGF)-AB with subnanomolar affinity from a randomized DNA library using in vitro selection. Individual ligands cloned from the affinity-enriched pool bind to PDGF-AB and PDGF-BB with comparably high affinity (Kd approximately 10(-10) M) and to PDGF-AA with lower affinity (> 10(-8) M), indicating specific recognition of the PDGF B-chain in the context of the hetero- or homodimer. The consensus secondary structure motif for most of the high-affinity ligands is a three-way helix junction with a three-nucleotide loop at the branch point. Photo-cross-linking experiments with 5-iodo-2'-deoxyuridine-substituted ligands establish a point contact between a thymidine nucleotide in the helix junction loop region and phenylalanine 84 of the PDGF-B chain. Representative minimal DNA ligands inhibit the binding of 125I-PDGF-BB but not of 125I-PDGF-AA to PDGF alpha- or beta-receptors expressed in porcine aortic endothelial (PAE) cells in a concentration-dependent manner with half-maximal effects of approximately 1 nM. The same ligands also exhibit a similar inhibitory effect on PDGF-BB-dependent [3H]thymidine incorporation in PAE cells expressing the PDGF beta-receptors. These DNA ligands represent a novel class of specific and potent antagonists of PDGF-BB and, by inference, PDGF-AB.

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Section: Discussionmentioning

confidence: 99%

Inhibitory DNA Ligands to Platelet-Derived Growth Factor B-Chain

et al. 1996

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“…Mutations in these residues might be responsible for differences in affinity and selectivity within the VEGF group. Because of the structural similarity between VEGF and PDGF, and supported by the mutagenesis data published so far, the same positions might be responsible for receptor recognition by PDGF [30,52,53]. (The sequences of PLGF, VEGF-B, VEGF-C, PDGF-A and PDGF-B were obtained from the Swissprot databank with accession numbers P49763, P49765, P49769, P04085 and P01127, respectively.)…”

Section: Biological Implicationsmentioning

confidence: 97%

“…This face consists of the short threestranded β sheet (strands β2, β5 and β6) and loop β1 to β2 of one monomer together with the N-terminal α helix and loop β3 to β4 of the second monomer. In PDGF, the residues that have thus far been implicated in receptor binding all map on the equivalent face [30,52,53].…”

Section: Receptor Bindingmentioning

confidence: 99%

The crystal structure of vascular endothelial growth factor (VEGF) refined to 1.93 Å resolution: multiple copy flexibility and receptor binding

Muller

Christinger²,

Keyt³

et al. 1997

Structure

213

198

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A comparison of the eight independent copies of VEGF in the asymmetric unit indicates the conformational space sampled by the protein in solution; the root mean square differences observed are similar to those seen in ensembles of the highest precision NMR structures. Mapping the receptor-binding determinants on a multiple sequence alignment of VEGF homologs, suggests the differences in specificity towards KDR and Flt-1 may derive from both sequence variation and changes in the flexibility of binding loops. The structure can also be used to predict possible receptor-binding determinants for related cystine knot growth factors, such as PDGF.

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“…The three loops critically involved in PDGFR binding are composed of hydrophobic (loop I), hydrophobic and cationic (loop II) and cationic (loop III) residues. Epitope mapping and mutagenesis studies [40][41][42][43][44][45] have shown that of the three loops, the residues in loop I are most important in the binding to PDGFR. In our previous two generations of calixarene derivatives, the combination of hydrophobic and acidic groups 28 turned out to be essential to achieve optimal binding affinity.…”

Section: Design and Syntheses Of Pdgf Antagonistsmentioning

confidence: 99%

Structure–activity studies on a library of potent calix[4]arene-based PDGF antagonists that inhibit PDGF-stimulated PDGFR tyrosine phosphorylation

et al. 2006

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Platelet-derived growth factor (PDGF) and its receptor PDGFR are required for tumor growth and angiogenesis, so disruption of the PDGF-PDGFR interaction should lead to starvation of tumors and reduction of tumor growth. Potent PDGF antagonists have been discovered through the synthesis of a series of calix[4]arene-based compounds that are designed to bind to the three-loop region of PDGF. The effect of lower-rim alkylation, linker and number of interacting head groups on the calix[4]arene scaffold on PDGF affinity and cellular activity has been investigated.

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Five PDGF B amino acid substitutions convert PDGF A to a PDGF B-like transforming molecule.

Cited by 42 publications

References 28 publications

Inhibitory DNA Ligands to Platelet-Derived Growth Factor B-Chain

Inhibitory DNA Ligands to Platelet-Derived Growth Factor B-Chain

The crystal structure of vascular endothelial growth factor (VEGF) refined to 1.93 Å resolution: multiple copy flexibility and receptor binding

Structure–activity studies on a library of potent calix[4]arene-based PDGF antagonists that inhibit PDGF-stimulated PDGFR tyrosine phosphorylation

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