View source for 8g04


==Structure of signaling thrombopoietin-MPL receptor complex==
<StructureSection load='8g04' size='340' side='right'caption='[[8g04]], [[Resolution|resolution]] 3.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8g04]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8G04 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8G04 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.4&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8g04 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8g04 OCA], [https://pdbe.org/8g04 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8g04 RCSB], [https://www.ebi.ac.uk/pdbsum/8g04 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8g04 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/TPO_HUMAN TPO_HUMAN] Defects in THPO are the cause of thrombocythemia type 1 (THCYT1) [MIM:[https://omim.org/entry/187950 187950]. A myeloproliferative disorder characterized by elevated platelet levels due to sustained proliferation of megakaryocytes, and frequently lead to thrombotic and haemorrhagic complications.<ref>PMID:9425899</ref> 
== Function ==
[https://www.uniprot.org/uniprot/TPO_HUMAN TPO_HUMAN] Lineage-specific cytokine affecting the proliferation and maturation of megakaryocytes from their committed progenitor cells. It acts at a late stage of megakaryocyte development. It may be the major physiological regulator of circulating platelets.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Thrombopoietin (THPO or TPO) is an essential cytokine for hematopoietic stem cell (HSC) maintenance and megakaryocyte differentiation. Here, we report the 3.4 A resolution cryoelectron microscopy structure of the extracellular TPO-TPO receptor (TpoR or MPL) signaling complex, revealing the basis for homodimeric MPL activation and providing a structural rationalization for genetic loss-of-function thrombocytopenia mutations. The structure guided the engineering of TPO variants (TPO(mod)) with a spectrum of signaling activities, from neutral antagonists to partial- and super-agonists. Partial agonist TPO(mod) decoupled JAK/STAT from ERK/AKT/CREB activation, driving a bias for megakaryopoiesis and platelet production without causing significant HSC expansion in mice and showing superior maintenance of human HSCs in vitro. These data demonstrate the functional uncoupling of the two primary roles of TPO, highlighting the potential utility of TPO(mod) in hematology research and clinical HSC transplantation.

Structure of the thrombopoietin-MPL receptor complex is a blueprint for biasing hematopoiesis.,Tsutsumi N, Masoumi Z, James SC, Tucker JA, Winkelmann H, Grey W, Picton LK, Moss L, Wilson SC, Caveney NA, Jude KM, Gati C, Piehler J, Hitchcock IS, Garcia KC Cell. 2023 Sep 14;186(19):4189-4203.e22. doi: 10.1016/j.cell.2023.07.037. Epub , 2023 Aug 25. PMID:37633268<ref>PMID:37633268</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8g04" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Garcia KC]]
[[Category: Gati C]]
[[Category: Jude KM]]
[[Category: Tsutsumi N]]