4ztu | pdb_00004ztu

Structural basis for processivity and antiviral drug toxicity in human mitochondrial DNA replicase

spinqualitylabelsall models 4ztu, resolution 3.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ztu is a 5 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: DCT, DOC, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease DPOG1_HUMAN Defects in POLG are the cause of progressive external ophthalmoplegia with mitochondrial DNA deletions autosomal dominant type 1 (PEOA1) [MIM: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. Defects in POLG are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions autosomal recessive (PEOB) [MIM:258450. PEOB is a severe form of progressive external ophthalmoplegia. It is clinically more heterogeneous than the autosomal dominant forms. Can be more severe. Defects in POLG are a cause of sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO) [MIM: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. Defects in POLG are the cause of mitochondrial DNA depletion syndrome type 4A (MTDPS4A) [MIM: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. Defects in POLG are the cause of mitochondrial DNA depletion syndrome type 4B (MTDPS4B) [MIM: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:256000. LS is a severe neurological disorder characterized by bilaterally symmetrical necrotic lesions in subcortical brain regions. Function DPOG1_HUMAN Involved in the replication of mitochondrial DNA. Associates with mitochondrial DNA. Publication Abstract from PubMed The human DNA polymerase gamma (Pol gamma) is responsible for DNA replication in mitochondria. Pol gamma is particularly susceptible to inhibition by dideoxynucleoside-based inhibitors designed to fight viral infection. Here, we report crystal structures of the replicating Pol gamma-DNA complex bound to either substrate or zalcitabine, an inhibitor used for HIV reverse transcriptase. The structures reveal that zalcitabine binds to the Pol gamma active site almost identically to the substrate dCTP, providing a structural basis for Pol gamma-mediated drug toxicity. When compared to the apo form, Pol gamma undergoes intra- and inter-subunit conformational changes upon formation of the ternary complex with primer/template DNA and substrate. We also find that the accessory subunit Pol gammaB, which lacks intrinsic enzymatic activity and does not contact the primer/template DNA directly, serves as an allosteric regulator of holoenzyme activities. The structures presented here suggest a mechanism for processivity of the holoenzyme and provide a model for understanding the deleterious effects of Pol gamma mutations in human disease. Crystal structures of the mitochondrial DNA polymerase, Pol gamma, in complex with substrate or antiviral inhibitor zalcitabine provide a basis for understanding Pol gamma-mediated drug toxicity. Structural basis for processivity and antiviral drug toxicity in human mitochondrial DNA replicase.,Szymanski MR, Kuznetsov VB, Shumate C, Meng Q, Lee YS, Patel G, Patel S, Yin YW EMBO J. 2015 Jul 14;34(14):1959-70. doi: 10.15252/embj.201591520. Epub 2015 Jun, 8. PMID:26056153 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also DNA polymerase 3D structures

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