View source for 8udk


==Human Mitochondrial DNA Polymerase gamma R853A Ternary Complex==
<StructureSection load='8udk' size='340' side='right'caption='[[8udk]], [[Resolution|resolution]] 3.43&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8udk]] is a 7 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8UDK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8UDK 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]] 3.43&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DCP:2-DEOXYCYTIDINE-5-TRIPHOSPHATE'>DCP</scene>, <scene name='pdbligand=DOC:2,3-DIDEOXYCYTIDINE-5-MONOPHOSPHATE'>DOC</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=8udk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8udk OCA], [https://pdbe.org/8udk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8udk RCSB], [https://www.ebi.ac.uk/pdbsum/8udk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8udk ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/DPOG1_HUMAN DPOG1_HUMAN] Defects in POLG are the cause of progressive external ophthalmoplegia with mitochondrial DNA deletions autosomal dominant type 1 (PEOA1) [MIM:[https://omim.org/entry/157640 157640]. Progressive external ophthalmoplegia is characterized by progressive weakness of ocular muscles and levator muscle of the upper eyelid. In a minority of cases, it is associated with skeletal myopathy, which predominantly involves axial or proximal muscles and which causes abnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A large proportion of chronic ophthalmoplegias are associated with other symptoms, leading to a multisystemic pattern of this disease. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism.<ref>PMID:12210792</ref> <ref>PMID:11897778</ref> <ref>PMID:15534189</ref> <ref>PMID:15351195</ref> <ref>PMID:17420318</ref> <ref>PMID:18575922</ref>   Defects in POLG are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions autosomal recessive (PEOB) [MIM:[https://omim.org/entry/258450 258450]. PEOB is a severe form of progressive external ophthalmoplegia. It is clinically more heterogeneous than the autosomal dominant forms. Can be more severe.<ref>PMID:15351195</ref> <ref>PMID:11431686</ref> <ref>PMID:12975295</ref> <ref>PMID:12872260</ref> <ref>PMID:14635118</ref> <ref>PMID:12707443</ref> <ref>PMID:12565911</ref> <ref>PMID:15349879</ref> <ref>PMID:15477547</ref> <ref>PMID:15917273</ref> <ref>PMID:16634032</ref> <ref>PMID:16401742</ref> <ref>PMID:16621917</ref> <ref>PMID:16639411</ref>   Defects in POLG are a cause of sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO) [MIM:[https://omim.org/entry/607459 607459]. SANDO is a systemic disorder resulting from mitochondrial dysfunction associated with mitochondrial depletion in skeletal muscle and peripheral nerve tissue. The clinical triad of symptoms consists of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis. However, the phenotype varies widely, even within the same family, and can also include myopathy, seizures, and hearing loss. An atypical form of the disease is characterized by headaches and/or seizures manifesting in childhood or adolescence, followed by development of cerebellar and sensory ataxia, dysarthria, progressive external ophthalmoplegia, and myoclonus in early adulthood.<ref>PMID:12565911</ref> <ref>PMID:15477547</ref> <ref>PMID:15917273</ref> <ref>PMID:16621917</ref> <ref>PMID:16639411</ref> <ref>PMID:14745080</ref> <ref>PMID:16080118</ref> <ref>PMID:15824347</ref> <ref>PMID:16919951</ref>   Defects in POLG are the cause of mitochondrial DNA depletion syndrome type 4A (MTDPS4A) [MIM:[https://omim.org/entry/203700 203700]; also called Alpers diffuse degeneration of cerebral gray matter with hepatic cirrhosis. An autosomal recessive hepatocerebral syndrome. The typical course of the disease includes severe developmental delay, intractable seizures, liver failure, and death in childhood. Refractory seizures, cortical blindness, progressive liver dysfunction, and acute liver failure after exposure to valproic acid are considered diagnostic features. The neuropathological hallmarks are neuronal loss, spongiform degeneration, and astrocytosis of the visual cortex. Liver biopsy results show steatosis, often progressing to cirrhosis.<ref>PMID:16621917</ref> <ref>PMID:16639411</ref> <ref>PMID:15122711</ref> <ref>PMID:15929042</ref> <ref>PMID:15689359</ref> <ref>PMID:18828154</ref>   Defects in POLG are the cause of mitochondrial DNA depletion syndrome type 4B (MTDPS4B) [MIM:[https://omim.org/entry/613662 613662]; also known as mitochondrial DNA depletion syndrome 4B MNGIE type or mitochondrial neurogastrointestinal encephalopathy syndrome POLG-related. An autosomal recessive progressive multisystem disorder clinically characterized by chronic gastrointestinal dysmotility and pseudo-obstruction, cachexia, progressive external ophthalmoplegia, axonal sensory ataxic neuropathy, and muscle weakness.  Defects in POLG are a cause of Leigh syndrome (LS) [MIM:[https://omim.org/entry/256000 256000]. LS is a severe neurological disorder characterized by bilaterally symmetrical necrotic lesions in subcortical brain regions.<ref>PMID:18828154</ref> 
== Function ==
[https://www.uniprot.org/uniprot/DPOG1_HUMAN DPOG1_HUMAN] Involved in the replication of mitochondrial DNA. Associates with mitochondrial DNA.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The replication accuracy of DNA polymerase gamma (Pol gamma) is essential for mitochondrial genome integrity. Mutation of human Pol gamma arginine-853 has been linked to neurological diseases. Although not a catalytic residue, Pol gamma arginine-853 mutants are void of polymerase activity. To identify the structural basis for the disease, we determined a crystal structure of the Pol gamma mutant ternary complex with correct incoming nucleotide 2'-deoxycytidine 5'-triphosphate (dCTP). Opposite to the wild type that undergoes open-to-closed conformational changes when bound to a correct nucleotide that is essential for forming a catalytically competent active site, the mutant complex failed to undergo the conformational change, and the dCTP did not base pair with its Watson-Crick complementary templating residue. Our studies revealed that arginine-853 coordinates an interaction network that aligns the 3'-end of primer and dCTP with the catalytic residues. Disruption of the network precludes the formation of Watson-Crick base pairing and closing of the active site, resulting in an inactive polymerase.

An interaction network in the polymerase active site is a prerequisite for Watson-Crick base pairing in Pol gamma.,Park J, Herrmann GK, Roy A, Shumate CK, Cisneros GA, Yin YW Sci Adv. 2024 May 24;10(21):eadl3214. doi: 10.1126/sciadv.adl3214. Epub 2024 May , 24. PMID:38787958<ref>PMID:38787958</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8udk" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Herrmann GK]]
[[Category: Park J]]
[[Category: Yin YW]]