7nx2: Difference between revisions
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==Unbound antigen-binding fragment (FAb) 324== | |||
<StructureSection load='7nx2' size='340' side='right'caption='[[7nx2]], [[Resolution|resolution]] 1.47Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7nx2]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NX2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NX2 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.47Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=7nx2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nx2 OCA], [https://pdbe.org/7nx2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nx2 RCSB], [https://www.ebi.ac.uk/pdbsum/7nx2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nx2 ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Anaplastic lymphoma kinase (ALK)(1) and the related leukocyte tyrosine kinase (LTK)(2) are recently deorphanized receptor tyrosine kinases(3). Together with their activating cytokines, ALKAL1 and ALKAL2(4-6) (also called FAM150A and FAM150B or AUGbeta and AUGalpha, respectively), they are involved in neural development(7), cancer(7-9) and autoimmune diseases(10). Furthermore, mammalian ALK recently emerged as a key regulator of energy expenditure and weight gain(11), consistent with a metabolic role for Drosophila ALK(12). Despite such functional pleiotropy and growing therapeutic relevance(13,14), structural insights into ALK and LTK and their complexes with cognate cytokines have remained scarce. Here we show that the cytokine-binding segments of human ALK and LTK comprise a novel architectural chimera of a permuted TNF-like module that braces a glycine-rich subdomain featuring a hexagonal lattice of long polyglycine type II helices. The cognate cytokines ALKAL1 and ALKAL2 are monomeric three-helix bundles, yet their binding to ALK and LTK elicits similar dimeric assemblies with two-fold symmetry, that tent a single cytokine molecule proximal to the cell membrane. We show that the membrane-proximal EGF-like domain dictates the apparent cytokine preference of ALK. Assisted by these diverse structure-function findings, we propose a structural and mechanistic blueprint for complexes of ALK family receptors, and thereby extend the repertoire of ligand-mediated dimerization mechanisms adopted by receptor tyrosine kinases. | |||
Structural basis of cytokine-mediated activation of ALK family receptors.,De Munck S, Provost M, Kurikawa M, Omori I, Mukohyama J, Felix J, Bloch Y, Abdel-Wahab O, Bazan JF, Yoshimi A, Savvides SN Nature. 2021 Oct 13. pii: 10.1038/s41586-021-03959-5. doi:, 10.1038/s41586-021-03959-5. PMID:34646012<ref>PMID:34646012</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 7nx2" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Antibody 3D structures|Antibody 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Mus musculus]] | |||
[[Category: De Munck S]] | |||
[[Category: Savvides SN]] | |||
Latest revision as of 15:40, 1 February 2024
Unbound antigen-binding fragment (FAb) 324Unbound antigen-binding fragment (FAb) 324
Structural highlights
Publication Abstract from PubMedAnaplastic lymphoma kinase (ALK)(1) and the related leukocyte tyrosine kinase (LTK)(2) are recently deorphanized receptor tyrosine kinases(3). Together with their activating cytokines, ALKAL1 and ALKAL2(4-6) (also called FAM150A and FAM150B or AUGbeta and AUGalpha, respectively), they are involved in neural development(7), cancer(7-9) and autoimmune diseases(10). Furthermore, mammalian ALK recently emerged as a key regulator of energy expenditure and weight gain(11), consistent with a metabolic role for Drosophila ALK(12). Despite such functional pleiotropy and growing therapeutic relevance(13,14), structural insights into ALK and LTK and their complexes with cognate cytokines have remained scarce. Here we show that the cytokine-binding segments of human ALK and LTK comprise a novel architectural chimera of a permuted TNF-like module that braces a glycine-rich subdomain featuring a hexagonal lattice of long polyglycine type II helices. The cognate cytokines ALKAL1 and ALKAL2 are monomeric three-helix bundles, yet their binding to ALK and LTK elicits similar dimeric assemblies with two-fold symmetry, that tent a single cytokine molecule proximal to the cell membrane. We show that the membrane-proximal EGF-like domain dictates the apparent cytokine preference of ALK. Assisted by these diverse structure-function findings, we propose a structural and mechanistic blueprint for complexes of ALK family receptors, and thereby extend the repertoire of ligand-mediated dimerization mechanisms adopted by receptor tyrosine kinases. Structural basis of cytokine-mediated activation of ALK family receptors.,De Munck S, Provost M, Kurikawa M, Omori I, Mukohyama J, Felix J, Bloch Y, Abdel-Wahab O, Bazan JF, Yoshimi A, Savvides SN Nature. 2021 Oct 13. pii: 10.1038/s41586-021-03959-5. doi:, 10.1038/s41586-021-03959-5. PMID:34646012[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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