6s4e: Difference between revisions

From Proteopedia
Jump to navigationJump to search
← Older editNewer edit →
OCA (talk | contribs)
Bots, Bureaucrats, journal, Administrators
3,329,986 edits
No edit summary
OCA (talk | contribs)
Bots, Bureaucrats, journal, Administrators
3,329,986 edits
No edit summary
Line 1: Line 1:


==Structure of human MTHFD2 in complex with TH7299==
==Structure of human MTHFD2 in complex with TH7299==
<StructureSection load='6s4e' size='340' side='right'caption='[[6s4e]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
<StructureSection load='6s4e' size='340' side='right'caption='[[6s4e]]' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6s4e]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6S4E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6S4E FirstGlance]. <br>
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6S4E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6S4E FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9L9:(2S)-2-[[4-[[2,4-BIS(AZANYL)-6-OXIDANYLIDENE-1H-PYRIMIDIN-5-YL]CARBAMOYLAMINO]PHENYL]CARBONYLAMINO]PENTANEDIOIC+ACID'>9L9</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
</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=6s4e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6s4e OCA], [https://pdbe.org/6s4e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6s4e RCSB], [https://www.ebi.ac.uk/pdbsum/6s4e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6s4e ProSAT]</span></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MTHFD2, NMDMC ([https://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'>[https://proteopedia.org/fgij/fg.htm?mol=6s4e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6s4e OCA], [https://pdbe.org/6s4e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6s4e RCSB], [https://www.ebi.ac.uk/pdbsum/6s4e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6s4e ProSAT]</span></td></tr>
</table>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors.
Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress.,Bonagas N, Gustafsson NMS, Henriksson M, Marttila P, Gustafsson R, Wiita E, Borhade S, Green AC, Vallin KSA, Sarno A, Svensson R, Gokturk C, Pham T, Jemth AS, Loseva O, Cookson V, Kiweler N, Sandberg L, Rasti A, Unterlass JE, Haraldsson M, Andersson Y, Scaletti ER, Bengtsson C, Paulin CBJ, Sanjiv K, Abdurakhmanov E, Pudelko L, Kunz B, Desroses M, Iliev P, Farnegardh K, Kramer A, Garg N, Michel M, Haggblad S, Jarvius M, Kalderen C, Jensen AB, Almlof I, Karsten S, Zhang SM, Haggblad M, Eriksson A, Liu J, Glinghammar B, Nekhotiaeva N, Klingegard F, Koolmeister T, Martens U, Llona-Minguez S, Moulson R, Nordstrom H, Parrow V, Dahllund L, Sjoberg B, Vargas IL, Vo DD, Wannberg J, Knapp S, Krokan HE, Arvidsson PI, Scobie M, Meiser J, Stenmark P, Berglund UW, Homan EJ, Helleday T Nat Cancer. 2022 Feb;3(2):156-172. doi: 10.1038/s43018-022-00331-y. Epub 2022 Feb, 28. PMID:35228749<ref>PMID:35228749</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6s4e" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Abdurakhmanov, E]]
[[Category: Abdurakhmanov E]]
[[Category: Andersson, Y]]
[[Category: Andersson Y]]
[[Category: Bengtsson, C]]
[[Category: Bengtsson C]]
[[Category: Bonagas, N]]
[[Category: Bonagas N]]
[[Category: Borhade, S]]
[[Category: Borhade S]]
[[Category: Desroses, M]]
[[Category: Desroses M]]
[[Category: Farnegardh, K]]
[[Category: Farnegardh K]]
[[Category: Garg, N]]
[[Category: Garg N]]
[[Category: Gokturk, C]]
[[Category: Gokturk C]]
[[Category: Gustafsson, N M]]
[[Category: Gustafsson NM]]
[[Category: Gustafsson, R]]
[[Category: Gustafsson R]]
[[Category: Haraldsson, M]]
[[Category: Haraldsson M]]
[[Category: Helleday, T]]
[[Category: Helleday T]]
[[Category: Henriksson, M]]
[[Category: Henriksson M]]
[[Category: Homan, E J]]
[[Category: Homan EJ]]
[[Category: Iliev, P]]
[[Category: Iliev P]]
[[Category: Jarvius, M]]
[[Category: Jarvius M]]
[[Category: Jemth, A S]]
[[Category: Jemth AS]]
[[Category: Kalderen, C]]
[[Category: Kalderen C]]
[[Category: Karsten, S]]
[[Category: Karsten S]]
[[Category: Klingegard, F]]
[[Category: Klingegard F]]
[[Category: Koolmeister, T]]
[[Category: Koolmeister T]]
[[Category: Llona-Minguez, S]]
[[Category: Llona-Minguez S]]
[[Category: Loseva, O]]
[[Category: Loseva O]]
[[Category: Martens, U]]
[[Category: Martens U]]
[[Category: Marttila, P]]
[[Category: Marttila P]]
[[Category: Michel, M]]
[[Category: Michel M]]
[[Category: Moulson, R]]
[[Category: Moulson R]]
[[Category: Nordstrom, H]]
[[Category: Nordstrom H]]
[[Category: Paulin, C]]
[[Category: Paulin C]]
[[Category: Pham, T]]
[[Category: Pham T]]
[[Category: Pudelko, L]]
[[Category: Pudelko L]]
[[Category: Rasti, A]]
[[Category: Rasti A]]
[[Category: Roos, A K]]
[[Category: Roos AK]]
[[Category: Sandberg, L]]
[[Category: Sandberg L]]
[[Category: Sarno, A]]
[[Category: Sarno A]]
[[Category: Scaletti, E R]]
[[Category: Scaletti ER]]
[[Category: Scobie, M]]
[[Category: Scobie M]]
[[Category: Sjoberg, B]]
[[Category: Sjoberg B]]
[[Category: Stenmark, P]]
[[Category: Stenmark P]]
[[Category: Svensson, R]]
[[Category: Svensson R]]
[[Category: Unterlass, J E]]
[[Category: Unterlass JE]]
[[Category: Vallin, K]]
[[Category: Vallin K]]
[[Category: Vo, D]]
[[Category: Vo D]]
[[Category: Warpman-Berglund, U]]
[[Category: Warpman-Berglund U]]
[[Category: Wiita, E]]
[[Category: Wiita E]]
[[Category: Oxidoreductase]]

Revision as of 14:42, 31 August 2022

Structure of human MTHFD2 in complex with TH7299

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "https://proteopedia.org/index.php?title=6s4e&oldid=3614799"