6y9b: Difference between revisions
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==Cryo-EM structure of trimeric human STEAP1 bound to three Fab120.545 fragments== | ==Cryo-EM structure of trimeric human STEAP1 bound to three Fab120.545 fragments== | ||
<StructureSection load='6y9b' size='340' side='right'caption='[[6y9b]]' scene=''> | <StructureSection load='6y9b' size='340' side='right'caption='[[6y9b]], [[Resolution|resolution]] 2.97Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Y9B OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6Y9B FirstGlance]. <br> | <table><tr><td colspan='2'>[[6y9b]] is a 9 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Y9B OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6Y9B FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6y9b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6y9b OCA], [http://pdbe.org/6y9b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6y9b RCSB], [http://www.ebi.ac.uk/pdbsum/6y9b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6y9b ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=XP4:1,2-DIMYRISTOYL-SN-GLYCERO-3-PHOSPHATE'>XP4</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">STEAP1, PRSS24, STEAP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6y9b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6y9b OCA], [http://pdbe.org/6y9b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6y9b RCSB], [http://www.ebi.ac.uk/pdbsum/6y9b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6y9b ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[http://www.uniprot.org/uniprot/STEA1_HUMAN STEA1_HUMAN]] Metalloreductase that has the ability to reduce both Fe(3+) to Fe(2+) and Cu(2+) to Cu(1+). Uses NAD(+) as acceptor.[UniProtKB:Q9CWR7] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is an integral membrane protein that is highly upregulated on the cell surface of several human cancers, making it a promising therapeutic target to manage these diseases. It shares sequence homology with three enzymes (STEAP2-4) that catalyze the NADPH-dependent reduction of iron(III). However, STEAP1 lacks an intracellular NADPH-binding domain and does not exhibit cellular ferric-reductase activity. Thus, both the molecular function of STEAP1 and its role in cancer progression remain elusive. Here, we present a ~3.0 A cryo-EM structure of trimeric human STEAP1 bound to three antigen-binding fragments (Fabs) of the clinically used antibody mAb120.545. The structure disclosed that STEAP1 adopts a reductase-like conformation and interacts with the Fabs through its extracellular helices. Enzymatic assays in human cells revealed that STEAP1 promotes iron(III) reduction when fused to the intracellular NADPH-binding domain of its family member STEAP4, suggesting that STEAP1 functions as a ferric reductase in STEAP hetero-trimers. Our work provides a foundation for deciphering the molecular mechanisms of STEAP1 and may be instrumental in the design of new therapeutic strategies to target STEAP1 in cancer. | |||
Cryo-EM structure and potential enzymatic function of human six-transmembrane epithelial antigen of the prostate 1.,Oosterheert W, Gros P J Biol Chem. 2020 May 14. pii: RA120.013690. doi: 10.1074/jbc.RA120.013690. PMID:32409586<ref>PMID:32409586</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6y9b" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Gros P]] | [[Category: Lk3 transgenic mice]] | ||
[[Category: Oosterheert W]] | [[Category: Gros, P]] | ||
[[Category: Oosterheert, W]] | |||
[[Category: Integral membrane protein heme-binding protein oxidoreductase antibody-antigen complex]] | |||
[[Category: Membrane protein]] | |||
Revision as of 10:43, 27 May 2020
Cryo-EM structure of trimeric human STEAP1 bound to three Fab120.545 fragmentsCryo-EM structure of trimeric human STEAP1 bound to three Fab120.545 fragments
Structural highlights
Function[STEA1_HUMAN] Metalloreductase that has the ability to reduce both Fe(3+) to Fe(2+) and Cu(2+) to Cu(1+). Uses NAD(+) as acceptor.[UniProtKB:Q9CWR7] Publication Abstract from PubMedSix-transmembrane epithelial antigen of the prostate 1 (STEAP1) is an integral membrane protein that is highly upregulated on the cell surface of several human cancers, making it a promising therapeutic target to manage these diseases. It shares sequence homology with three enzymes (STEAP2-4) that catalyze the NADPH-dependent reduction of iron(III). However, STEAP1 lacks an intracellular NADPH-binding domain and does not exhibit cellular ferric-reductase activity. Thus, both the molecular function of STEAP1 and its role in cancer progression remain elusive. Here, we present a ~3.0 A cryo-EM structure of trimeric human STEAP1 bound to three antigen-binding fragments (Fabs) of the clinically used antibody mAb120.545. The structure disclosed that STEAP1 adopts a reductase-like conformation and interacts with the Fabs through its extracellular helices. Enzymatic assays in human cells revealed that STEAP1 promotes iron(III) reduction when fused to the intracellular NADPH-binding domain of its family member STEAP4, suggesting that STEAP1 functions as a ferric reductase in STEAP hetero-trimers. Our work provides a foundation for deciphering the molecular mechanisms of STEAP1 and may be instrumental in the design of new therapeutic strategies to target STEAP1 in cancer. Cryo-EM structure and potential enzymatic function of human six-transmembrane epithelial antigen of the prostate 1.,Oosterheert W, Gros P J Biol Chem. 2020 May 14. pii: RA120.013690. doi: 10.1074/jbc.RA120.013690. PMID:32409586[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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