7ue3: Difference between revisions

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<table><tr><td colspan='2'>[[7ue3]] 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=7UE3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UE3 FirstGlance]. <br>
<table><tr><td colspan='2'>[[7ue3]] 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=7UE3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UE3 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]] 1.56&#8491;</td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.56&#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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ND6:6-[4-({4-[(2R)-1-hydroxypropan-2-yl]phenyl}acetyl)piperazin-1-yl]pyridazine-3-carbonitrile'>ND6</scene></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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ND6:6-[4-[2-[4-[(2~{R})-1-oxidanylpropan-2-yl]phenyl]ethanoyl]piperazin-1-yl]pyridazine-3-carbonitrile'>ND6</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=7ue3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ue3 OCA], [https://pdbe.org/7ue3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ue3 RCSB], [https://www.ebi.ac.uk/pdbsum/7ue3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ue3 ProSAT]</span></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=7ue3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ue3 OCA], [https://pdbe.org/7ue3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ue3 RCSB], [https://www.ebi.ac.uk/pdbsum/7ue3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ue3 ProSAT]</span></td></tr>
</table>
</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 7ue3" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Pantothenate kinase 3D structures|Pantothenate kinase 3D structures]]
*[[Pantothenate kinase 3D structures|Pantothenate kinase 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>

Latest revision as of 12:38, 9 October 2024

PANK3 complex structure with compound PZ-3804PANK3 complex structure with compound PZ-3804

Structural highlights

7ue3 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 1.56Å
Ligands:, , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PANK3_HUMAN Plays a role in the physiological regulation of the intracellular CoA concentration (By similarity).

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[1]

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

See Also

References

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

7ue3, resolution 1.56Å

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