9n3o

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of PRMT5:MEP50 in complex with MTA and oxamide compound 14

Structural highlights

9n3o is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.37Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MEP50_HUMAN Non-catalytic component of the 20S PRMT5-containing methyltransferase complex, which modifies specific arginines to dimethylarginines in several spliceosomal Sm proteins and histones. This modification targets Sm proteins to the survival of motor neurons (SMN) complex for assembly into small nuclear ribonucleoprotein core particles. Might play a role in transcription regulation. The 20S PRMT5-containing methyltransferase complex also methylates the Piwi proteins (PIWIL1, PIWIL2 and PIWIL4), methylation of Piwi proteins being required for the interaction with Tudor domain-containing proteins and subsequent localization to the meiotic nuage.^[1] ^[2]

Publication Abstract from PubMed

The gene encoding for MTAP is one of the most commonly deleted genes in cancer, occurring in approximately 10-15% of all human cancer. We have previously described the discovery of TNG908, a brain-penetrant clinical-stage compound that selectively targets MTAP-deleted cancer cells by binding to and inhibiting PRMT5 cooperatively with MTA, which is present in elevated concentrations in MTAP-deleted cells. Herein we describe the discovery of TNG462, a more potent and selective MTA-cooperative PRMT5 inhibitor with improved DMPK properties that is selective for MTAP-deleted cancers and is currently in Phase I/II clinical trials.

Discovery of TNG462: A Highly Potent and Selective MTA-Cooperative PRMT5 Inhibitor to Target Cancers with MTAP Deletion.,Cottrell KM, Briggs KJ, Tsai A, Tonini MR, Whittington DA, Gong S, Liang C, McCarren P, Zhang M, Zhang W, Huang A, Maxwell JP J Med Chem. 2025 Mar 4. doi: 10.1021/acs.jmedchem.4c03067. PMID:40035511^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Friesen WJ, Wyce A, Paushkin S, Abel L, Rappsilber J, Mann M, Dreyfuss G. A novel WD repeat protein component of the methylosome binds Sm proteins. J Biol Chem. 2002 Mar 8;277(10):8243-7. Epub 2001 Dec 26. PMID:11756452 doi:http://dx.doi.org/10.1074/jbc.M109984200
↑ Antonysamy S, Bonday Z, Campbell RM, Doyle B, Druzina Z, Gheyi T, Han B, Jungheim LN, Qian Y, Rauch C, Russell M, Sauder JM, Wasserman SR, Weichert K, Willard FS, Zhang A, Emtage S. Crystal structure of the human PRMT5:MEP50 complex. Proc Natl Acad Sci U S A. 2012 Oct 30;109(44):17960-5. doi:, 10.1073/pnas.1209814109. Epub 2012 Oct 15. PMID:23071334 doi:http://dx.doi.org/10.1073/pnas.1209814109
↑ Cottrell KM, Briggs KJ, Tsai A, Tonini MR, Whittington DA, Gong S, Liang C, McCarren P, Zhang M, Zhang W, Huang A, Maxwell JP. Discovery of TNG462: A Highly Potent and Selective MTA-Cooperative PRMT5 Inhibitor to Target Cancers with MTAP Deletion. J Med Chem. 2025 Mar 4. PMID:40035511 doi:10.1021/acs.jmedchem.4c03067

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/9n3o"

Categories: Homo sapiens | Large Structures | Whittington DA

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9n3o is ON HOLD
+==Crystal structure of PRMT5:MEP50 in complex with MTA and oxamide compound 14==
+<StructureSection load='9n3o' size='340' side='right'caption='[[9n3o]], [[Resolution|resolution]] 2.37&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9n3o]] is a 2 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=9N3O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9N3O 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]] 2.37&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1BV4:N-(4-amino-1H-pyrazolo[4,3-c]pyridin-7-yl)-2-[(2R,5S)-2-(1,3-benzothiazol-5-yl)-5-methylpiperidin-1-yl]-2-oxoacetamide'>A1BV4</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MTA:5-DEOXY-5-METHYLTHIOADENOSINE'>MTA</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=9n3o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9n3o OCA], [https://pdbe.org/9n3o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9n3o RCSB], [https://www.ebi.ac.uk/pdbsum/9n3o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9n3o ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/MEP50_HUMAN MEP50_HUMAN] Non-catalytic component of the 20S PRMT5-containing methyltransferase complex, which modifies specific arginines to dimethylarginines in several spliceosomal Sm proteins and histones. This modification targets Sm proteins to the survival of motor neurons (SMN) complex for assembly into small nuclear ribonucleoprotein core particles. Might play a role in transcription regulation. The 20S PRMT5-containing methyltransferase complex also methylates the Piwi proteins (PIWIL1, PIWIL2 and PIWIL4), methylation of Piwi proteins being required for the interaction with Tudor domain-containing proteins and subsequent localization to the meiotic nuage.<ref>PMID:11756452</ref> <ref>PMID:23071334</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The gene encoding for MTAP is one of the most commonly deleted genes in cancer, occurring in approximately 10-15% of all human cancer. We have previously described the discovery of TNG908, a brain-penetrant clinical-stage compound that selectively targets MTAP-deleted cancer cells by binding to and inhibiting PRMT5 cooperatively with MTA, which is present in elevated concentrations in MTAP-deleted cells. Herein we describe the discovery of TNG462, a more potent and selective MTA-cooperative PRMT5 inhibitor with improved DMPK properties that is selective for MTAP-deleted cancers and is currently in Phase I/II clinical trials.
-Authors: Whittington, D.A.
+Discovery of TNG462: A Highly Potent and Selective MTA-Cooperative PRMT5 Inhibitor to Target Cancers with MTAP Deletion.,Cottrell KM, Briggs KJ, Tsai A, Tonini MR, Whittington DA, Gong S, Liang C, McCarren P, Zhang M, Zhang W, Huang A, Maxwell JP J Med Chem. 2025 Mar 4. doi: 10.1021/acs.jmedchem.4c03067. PMID:40035511<ref>PMID:40035511</ref>
-Description: Crystal structure of PRMT5:MEP50 in complex with MTA and oxamide compound 14
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Whittington, D.A]]
+<div class="pdbe-citations 9n3o" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Whittington DA]]

9n3o

From Proteopedia

Current revision

Crystal structure of PRMT5:MEP50 in complex with MTA and oxamide compound 14

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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