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| | == Structural highlights == | | == Structural highlights == |
| | <table><tr><td colspan='2'>[[3ikm]] is a 6 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=3IKM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3IKM FirstGlance]. <br> | | <table><tr><td colspan='2'>[[3ikm]] is a 6 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=3IKM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3IKM FirstGlance]. <br> |
| - | </td></tr><tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/DNA-directed_DNA_polymerase DNA-directed DNA polymerase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.7 2.7.7.7] </span></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]] 3.24Å</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=3ikm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ikm OCA], [https://pdbe.org/3ikm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ikm RCSB], [https://www.ebi.ac.uk/pdbsum/3ikm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ikm 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=3ikm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ikm OCA], [https://pdbe.org/3ikm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ikm RCSB], [https://www.ebi.ac.uk/pdbsum/3ikm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ikm ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == 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> [[https://www.uniprot.org/uniprot/DPOG2_HUMAN DPOG2_HUMAN]] Defects in POLG2 are the cause of progressive external ophthalmoplegia with mitochondrial DNA deletions autosomal dominant type 4 (PEOA4) [MIM:[https://omim.org/entry/610131 610131]]. 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:16685652</ref>
| + | [https://www.uniprot.org/uniprot/DPOG2_HUMAN DPOG2_HUMAN] Defects in POLG2 are the cause of progressive external ophthalmoplegia with mitochondrial DNA deletions autosomal dominant type 4 (PEOA4) [MIM:[https://omim.org/entry/610131 610131]. 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:16685652</ref> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/DPOG1_HUMAN DPOG1_HUMAN]] Involved in the replication of mitochondrial DNA. Associates with mitochondrial DNA. [[https://www.uniprot.org/uniprot/DPOG2_HUMAN DPOG2_HUMAN]] Mitochondrial polymerase processivity subunit. Stimulates the polymerase and exonuclease activities, and increases the processivity of the enzyme. Binds to ss-DNA.
| + | [https://www.uniprot.org/uniprot/DPOG2_HUMAN DPOG2_HUMAN] Mitochondrial polymerase processivity subunit. Stimulates the polymerase and exonuclease activities, and increases the processivity of the enzyme. Binds to ss-DNA. |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| Line 21: |
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| | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3ikm ConSurf]. | | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3ikm ConSurf]. |
| | <div style="clear:both"></div> | | <div style="clear:both"></div> |
| - | <div style="background-color:#fffaf0;"> | |
| - | == Publication Abstract from PubMed == | |
| - | Human mitochondrial DNA polymerase (Pol gamma) is the sole replicase in mitochondria. Pol gamma is vulnerable to nonselective antiretroviral drugs and is increasingly associated with mutations found in patients with mitochondriopathies. We determined crystal structures of the human heterotrimeric Pol gamma holoenzyme and, separately, a variant of its processivity factor, Pol gammaB. The holoenzyme structure reveals an unexpected assembly of the mitochondrial DNA replicase where the catalytic subunit Pol gammaA interacts with its processivity factor primarily via a domain that is absent in all other DNA polymerases. This domain provides a structural module for supporting both the intrinsic processivity of the catalytic subunit alone and the enhanced processivity of holoenzyme. The Pol gamma structure also provides a context for interpreting the phenotypes of disease-related mutations in the polymerase and establishes a foundation for understanding the molecular basis of toxicity of anti-retroviral drugs targeting HIV reverse transcriptase. | |
| | | | |
| - | Structural insight into processive human mitochondrial DNA synthesis and disease-related polymerase mutations.,Lee YS, Kennedy WD, Yin YW Cell. 2009 Oct 16;139(2):312-24. PMID:19837034<ref>PMID:19837034</ref>
| + | ==See Also== |
| - | | + | *[[DNA polymerase 3D structures|DNA polymerase 3D structures]] |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 3ikm" style="background-color:#fffaf0;"></div>
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: DNA-directed DNA polymerase]] | |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Kennedy, W D]] | + | [[Category: Kennedy WD]] |
| - | [[Category: Lee, Y S]] | + | [[Category: Lee Y-S]] |
| - | [[Category: Yin, Y W]] | + | [[Category: Yin YW]] |
| - | [[Category: Disease mutation]]
| + | |
| - | [[Category: Dna replication]]
| + | |
| - | [[Category: Dna-binding]]
| + | |
| - | [[Category: Dna-directed dna polymerase]]
| + | |
| - | [[Category: Human mitochondrial dna polymerase]]
| + | |
| - | [[Category: Magnesium]]
| + | |
| - | [[Category: Mitochondrion]]
| + | |
| - | [[Category: Neuropathy]]
| + | |
| - | [[Category: Nucleotidyltransferase]]
| + | |
| - | [[Category: Progressive external ophthalmoplegia]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Transit peptide]]
| + | |
