Crystal structure of human platelet-derived growth factor BB.

Oefner, Christian; D’Arcy, Allan; Winkler, Fritz K.; Eggimann, Bernhard; Hosang, Markus

doi:10.1002/j.1460-2075.1992.tb05485.x

Cited by 211 publications

(148 citation statements)

References 57 publications

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“…Finally, direct and competitive ELISAs were performed with serum samples from 29 consecutive patients with SLE (SLE Disease Activity Index range [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. The distribution of PDGFRa binding in SLE serum was comparable to that in healthy control serum, as determined by direct ELISA with PDGFRa-His.…”

Section: Epitope Specificity Of Anti-pdgfra Autoantibodies In Sscmentioning

confidence: 99%

Epitope Specificity Determines Pathogenicity and Detectability of Anti–Platelet‐Derived Growth Factor Receptor α Autoantibodies in Systemic Sclerosis

Moroncini

Grieco

Nacci

et al. 2015

Arthritis & Rheumatology

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Objective. To identify the epitopes recognized by autoantibodies targeting platelet-derived growth factor receptor a (PDGFRa) in systemic sclerosis (SSc) and develop novel assays for detection of serum antiPDGFRa autoantibodies.Methods. Epstein-Barr virus-immortalized B cells from 1 patient with SSc (designated PAM) were screened for expression of IgG binding to PDGFRa and induction of reactive oxygen species in fibroblasts. The variable regions of anti-PDGFRa IgG were cloned into an IgG expression vector to generate distinct recombinant human monoclonal autoantibodies (mAb), which were characterized by binding and functional assays. The epitopes of anti-PDGFRa recombinant human mAb were defined by molecular docking, surface plasmon resonance binding assays, screening of a conformational peptide library spanning the PDGFRa extracellular domains, and expression analyses of alanine-scanned PDGFRa mutants. Direct or competitive enzyme-linked immunosorbent assays were established to detect all serum anti-PDGFRa autoantibodies or, selectively, the agonistic ones.Results. Three types of anti-PDGFRa recombinant human mAb, with the same V H but distinct V L chains, were generated. Nonagonistic V H PAM-V k 13B8 recognized 1 linear epitope, whereas agonistic V H PAM-V l 16F4 and V H PAM-V k 16F4 recognized 2 distinct conformational epitopes. Serum anti-PDGFRa antibodies were detected in 66 of 70 patients with SSc, 63 of 130 healthy controls, 11 of 26 patients with primary Raynaud's phenomenon (RP), and 13 of 29 patients with systemic lupus erythematosus (SLE). Serum V H PAM-V k 16F4-like antibodies were found in 24 of 34 patients with SSc, but not in healthy controls, patients with primary RP, or patients with SLE. Peptides composing the V H PAM-V k 16F4 epitope inhibited PDGFRa signaling triggered by serum IgG from SSc patients.Conclusion. Agonistic anti-PDGFRa autoantibodies are enriched in SSc sera and recognize specific conformational epitopes that can be used to discriminate agonistic from nonagonistic antibodies and block PDGFRa signaling in patients with SSc.

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Section: Epitope Specificity Of Anti-pdgfra Autoantibodies In Sscmentioning

confidence: 99%

Epitope Specificity Determines Pathogenicity and Detectability of Anti–Platelet‐Derived Growth Factor Receptor α Autoantibodies in Systemic Sclerosis

Moroncini

Grieco

Nacci

et al. 2015

Arthritis & Rheumatology

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“…Daopin et al (1992) showed that three disulfides present in &nerve growth factor and transforming growth factor-6 can be superimposed to within 1 A , even though only two other residues were conserved in these two topologically related structures. Another predominantly &sheet cytokine, platelet-derived growth factor, may also show a similar arrangement of disulfides, although detailed comparisons have not yet been presented (Oefner et al, 1992). It is clear that the role of the disulfides in preserving structural integrity of these two classes of cytokines must be completely different.…”

Section: Disulfide Bondsmentioning

confidence: 99%

Hematopoietic cytokines: Similarities and differences in the structures, with implications for receptor binding

1993

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Crystal and NMR structures of helical cytokines-interleukin-4 (IL-4), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-2 (IL-2)-have been compared. Root mean square deviations in the C, coordinates for the conserved regions of the helices were 1-2 A between different cytokines, about twice the differences observed for independently determined crystal and solution structures of IL-4. Considerable similarity in amino acid sequence in the areas expected to interact with the receptors was detected, and the available mutagenesis data for these cytokines were correlated with structure conservation. Models of cytokine-receptor interactions were postulated for IL-4 based on its structure as well as on the published structure of human growth hormone interacting with its receptors (de Vos, A.M., Ultsch, M., & Kossiakoff, A.A., 1992, Science 255, 306-312). Patches of positively charged residues on the surfaces of helices C and D of IL-4 may be responsible for the interactions with the negatively charged residues found in the complementary parts of the IL-4 receptors.

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“…All VEGFs are antiparallel, cystine-knot polypeptide dimers that are covalently linked by two intermolecular disulfide bonds (16)(17)(18)(19). In VEGF-C and VEGF-D, this VEGF homology domain is flanked by C-and N-terminal propeptides that are sequentially cleaved, giving rise to VEGF homologs with distinct functions.…”

mentioning

confidence: 99%

Structural determinants of growth factor binding and specificity by VEGF receptor 2

Leppänen

Prota

Jeltsch

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

162

209

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Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel formation through activation of three receptor tyrosine kinases, VEGFR-1, -2, and -3. The extracellular domain of VEGF receptors consists of seven immunoglobulin homology domains, which, upon ligand binding, promote receptor dimerization. Dimerization initiates transmembrane signaling, which activates the intracellular tyrosine kinase domain of the receptor. VEGF-C stimulates lymphangiogenesis and contributes to pathological angiogenesis via VEGFR-3. However, proteolytically processed VEGF-C also stimulates VEGFR-2, the predominant transducer of signals required for physiological and pathological angiogenesis. Here we present the crystal structure of VEGF-C bound to the VEGFR-2 high-affinity-binding site, which consists of immunoglobulin homology domains D2 and D3. This structure reveals a symmetrical 2∶2 complex, in which left-handed twisted receptor domains wrap around the 2-fold axis of VEGF-C. In the VEGFs, receptor specificity is determined by an N-terminal alpha helix and three peptide loops. Our structure shows that two of these loops in VEGF-C bind to VEGFR-2 subdomains D2 and D3, while one interacts primarily with D3. Additionally, the N-terminal helix of VEGF-C interacts with D2, and the groove separating the two VEGF-C monomers binds to the D2/D3 linker. VEGF-C, unlike VEGF-A, does not bind VEGFR-1. We therefore created VEGFR-1/VEGFR-2 chimeric proteins to further study receptor specificity. This biochemical analysis, together with our structural data, defined VEGFR-2 residues critical for the binding of VEGF-A and VEGF-C. Our results provide significant insights into the structural features that determine the high affinity and specificity of VEGF/VEGFR interactions.

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Crystal structure of human platelet-derived growth factor BB.

Cited by 211 publications

References 57 publications

Epitope Specificity Determines Pathogenicity and Detectability of Anti–Platelet‐Derived Growth Factor Receptor α Autoantibodies in Systemic Sclerosis

Epitope Specificity Determines Pathogenicity and Detectability of Anti–Platelet‐Derived Growth Factor Receptor α Autoantibodies in Systemic Sclerosis

Hematopoietic cytokines: Similarities and differences in the structures, with implications for receptor binding

Structural determinants of growth factor binding and specificity by VEGF receptor 2

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