6R0X
The extracellular domain of G6b-B in complex with Fab fragment and DP12 heparin oligosaccharide.
Summary for 6R0X
| Entry DOI | 10.2210/pdb6r0x/pdb |
| Descriptor | antibody fab fragment heavy chain, antibody fab fragment light chain, Megakaryocyte and platelet inhibitory receptor G6b, ... (5 entities in total) |
| Functional Keywords | platelets, signaling, itim-receptor, g6b-b, heparin, blood clotting |
| Biological source | Homo sapiens More |
| Total number of polymer chains | 6 |
| Total formula weight | 131714.53 |
| Authors | Ogg, D.J.,McMiken, H.J.,Howard, T.D. (deposition date: 2019-03-13, release date: 2019-09-04, Last modification date: 2024-10-23) |
| Primary citation | Vogtle, T.,Sharma, S.,Mori, J.,Nagy, Z.,Semeniak, D.,Scandola, C.,Geer, M.J.,Smith, C.W.,Lane, J.,Pollack, S.,Lassila, R.,Jouppila, A.,Barr, A.J.,Ogg, D.J.,Howard, T.D.,McMiken, H.J.,Warwicker, J.,Geh, C.,Rowlinson, R.,Abbott, W.M.,Eckly, A.,Schulze, H.,Wright, G.J.,Mazharian, A.,Futterer, K.,Rajesh, S.,Douglas, M.R.,Senis, Y.A. Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B. Elife, 8:-, 2019 Cited by PubMed Abstract: The immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor G6b-B is critical for platelet production and activation. Loss of G6b-B results in severe macrothrombocytopenia, myelofibrosis and aberrant platelet function in mice and humans. Using a combination of immunohistochemistry, affinity chromatography and proteomics, we identified the extracellular matrix heparan sulfate (HS) proteoglycan perlecan as a G6b-B binding partner. Subsequent in vitro biochemical studies and a cell-based genetic screen demonstrated that the interaction is specifically mediated by the HS chains of perlecan. Biophysical analysis revealed that heparin forms a high-affinity complex with G6b-B and mediates dimerization. Using platelets from humans and genetically modified mice, we demonstrate that binding of G6b-B to HS and multivalent heparin inhibits platelet and megakaryocyte function by inducing downstream signaling via the tyrosine phosphatases Shp1 and Shp2. Our findings provide novel insights into how G6b-B is regulated and contribute to our understanding of the interaction of megakaryocytes and platelets with glycans. PubMed: 31436532DOI: 10.7554/eLife.46840 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.13 Å) |
Structure validation
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