9bkm

From Proteopedia

(Difference between revisions)

Current revision

DHODH in complex with Ligand 10

Structural highlights

9bkm is a 1 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 2.08Å
Ligands:	, , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

PYRD_HUMAN Defects in DHODH are the cause of postaxial acrofacial dysostosis (POADS) [MIM:263750; also known as Miller syndrome. POADS is characterized by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the posterior elements of the limbs, coloboma of the eyelids and supernumerary nipples. POADS is a very rare disorder: only 2 multiplex families, each consisting of 2 affected siblings born to unaffected, nonconsanguineous parents, have been described among a total of around 30 reported cases.^[1]

Function

PYRD_HUMAN Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.

Publication Abstract from PubMed

Acute myelogenous leukemia (AML), a heterogeneous disease of the blood and bone marrow, is characterized by the inability of myeloblasts to differentiate into mature cell types. Dihydroorotate dehydrogenase (DHODH) is an enzyme well-known in the pyrimidine biosynthesis pathway and preclinical findings demonstrated that DHODH is a metabolic vulnerability in AML as inhibitors can induce differentiation across multiple AML subtypes. As a result of virtual screening and structure-based drug design approaches, a novel series of isoquinolinone DHODH inhibitors was identified. Further lead optimization afforded JNJ-74856665 as an orally bioavailable, potent, and selective DHODH inhibitor with favorable physicochemical properties selected for clinical development in patients with AML and myelodysplastic syndromes (MDS).

Discovery of JNJ-74856665: A Novel Isoquinolinone DHODH Inhibitor for the Treatment of AML.,DeRatt LG, Zhang Z, Pietsch C, Cisar JS, Zhang X, Wang W, Tanner A, Matico R, Shaffer P, Jacoby E, Kazmi F, Shukla N, Bush TL, Patrick A, Philippar U, Attar R, Edwards JP, Kuduk SD J Med Chem. 2024 Jun 18. doi: 10.1021/acs.jmedchem.4c00809. PMID:38889244^[2]

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

References

↑ Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK, Dent KM, Huff CD, Shannon PT, Jabs EW, Nickerson DA, Shendure J, Bamshad MJ. Exome sequencing identifies the cause of a mendelian disorder. Nat Genet. 2010 Jan;42(1):30-5. doi: 10.1038/ng.499. Epub 2009 Nov 13. PMID:19915526 doi:10.1038/ng.499
↑ DeRatt LG, Zhang Z, Pietsch C, Cisar JS, Zhang X, Wang W, Tanner A, Matico R, Shaffer P, Jacoby E, Kazmi F, Shukla N, Bush TL, Patrick A, Philippar U, Attar R, Edwards JP, Kuduk SD. Discovery of JNJ-74856665: A Novel Isoquinolinone DHODH Inhibitor for the Treatment of AML. J Med Chem. 2024 Jun 18. PMID:38889244 doi:10.1021/acs.jmedchem.4c00809

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

Categories: Homo sapiens | Large Structures | Shaffer PL

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9bkm is ON HOLD  until Paper Publication
+==DHODH in complex with Ligand 10==
+<StructureSection load='9bkm' size='340' side='right'caption='[[9bkm]], [[Resolution|resolution]] 2.08&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9bkm]] is a 1 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=9BKM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9BKM 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]] 2.08&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1AQM:(2M,6P)-2-(2-chloro-6-fluorophenyl)-6-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-7-fluoro-4-(propan-2-yl)isoquinolin-1(2H)-one'>A1AQM</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene>, <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=9bkm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9bkm OCA], [https://pdbe.org/9bkm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9bkm RCSB], [https://www.ebi.ac.uk/pdbsum/9bkm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9bkm ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/PYRD_HUMAN PYRD_HUMAN] Defects in DHODH are the cause of postaxial acrofacial dysostosis (POADS) [MIM:[https://omim.org/entry/263750 263750]; also known as Miller syndrome. POADS is characterized by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the posterior elements of the limbs, coloboma of the eyelids and supernumerary nipples. POADS is a very rare disorder: only 2 multiplex families, each consisting of 2 affected siblings born to unaffected, nonconsanguineous parents, have been described among a total of around 30 reported cases.<ref>PMID:19915526</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/PYRD_HUMAN PYRD_HUMAN] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Acute myelogenous leukemia (AML), a heterogeneous disease of the blood and bone marrow, is characterized by the inability of myeloblasts to differentiate into mature cell types. Dihydroorotate dehydrogenase (DHODH) is an enzyme well-known in the pyrimidine biosynthesis pathway and preclinical findings demonstrated that DHODH is a metabolic vulnerability in AML as inhibitors can induce differentiation across multiple AML subtypes. As a result of virtual screening and structure-based drug design approaches, a novel series of isoquinolinone DHODH inhibitors was identified. Further lead optimization afforded JNJ-74856665 as an orally bioavailable, potent, and selective DHODH inhibitor with favorable physicochemical properties selected for clinical development in patients with AML and myelodysplastic syndromes (MDS).
-Authors: Shaffer, P.L.
+Discovery of JNJ-74856665: A Novel Isoquinolinone DHODH Inhibitor for the Treatment of AML.,DeRatt LG, Zhang Z, Pietsch C, Cisar JS, Zhang X, Wang W, Tanner A, Matico R, Shaffer P, Jacoby E, Kazmi F, Shukla N, Bush TL, Patrick A, Philippar U, Attar R, Edwards JP, Kuduk SD J Med Chem. 2024 Jun 18. doi: 10.1021/acs.jmedchem.4c00809. PMID:38889244<ref>PMID:38889244</ref>
-Description: DHODH in complex with Ligand 10
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Shaffer, P.L]]
+<div class="pdbe-citations 9bkm" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Shaffer PL]]

9bkm

From Proteopedia

Current revision

DHODH in complex with Ligand 10

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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