View source for 7ue5


==PANK3 complex structure with compound PZ-3741==
<StructureSection load='7ue5' size='340' side='right'caption='[[7ue5]], [[Resolution|resolution]] 1.63&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7ue5]] 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=7UE5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UE5 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]] 1.63&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=Y88:6-[4-[2-[4-[(2~{R})-1,1,1-tris(fluoranyl)propan-2-yl]phenyl]ethanoyl]piperazin-1-yl]pyridazine-3-carbonitrile'>Y88</scene>, <scene name='pdbligand=Y99:6-[4-({4-[(2S)-1,1,1-trifluoropropan-2-yl]phenyl}acetyl)piperazin-1-yl]pyridazine-3-carbonitrile'>Y99</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=7ue5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ue5 OCA], [https://pdbe.org/7ue5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ue5 RCSB], [https://www.ebi.ac.uk/pdbsum/7ue5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ue5 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PANK3_HUMAN PANK3_HUMAN] Plays a role in the physiological regulation of the intracellular CoA concentration (By similarity).
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Conversion of pantothenate to phosphopantothenate in humans is the first dedicated step in the coenzyme A (CoA) biosynthesis pathway and is mediated by four isoforms of pantothenate kinase. These enzymes are allosterically regulated by acyl-CoA levels, which control the rate of CoA biosynthesis. Small molecule activators of the PANK enzymes that overcome feedback suppression increase CoA levels in cultured cells and animals and have shown great potential for the treatment of pantothenate kinase-associated neurodegeneration and propionic acidemias. In this study, we detail the further optimization of PANK pyridazine activators using structure-guided design and focus on the cellular CoA activation potential, metabolic stability, and solubility as the primary drivers of the structure-activity relationship. These studies led to the prioritization of three late-stage preclinical lead PANK modulators with improved pharmacokinetic profiles and the ability to substantially increase brain CoA levels. Compound 22 (BBP-671) eventually advanced into clinical testing for the treatment of PKAN and propionic acidemia.

Development of Brain Penetrant Pyridazine Pantothenate Kinase Activators.,Tangallapally R, Subramanian C, Yun MK, Edwards A, Sharma LK, Yang L, Creed K, Wang J, Jackowski S, Rock CO, White SW, Lee RE J Med Chem. 2024 Aug 22;67(16):14432-14442. doi: 10.1021/acs.jmedchem.4c01211. , Epub 2024 Aug 13. PMID:39136313<ref>PMID:39136313</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7ue5" style="background-color:#fffaf0;"></div>

==See Also==
*[[Pantothenate kinase 3D structures|Pantothenate kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Lee RE]]
[[Category: White SW]]
[[Category: Yun M]]