| Structural highlights
2im3 is a 1 chain structure with sequence from Human poliovirus 1 mahoney. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , |
| NonStd Res: | |
| Related: | 1ra7, 1ra6, 2ily, 2ilz, 2im0, 2im1, 2im2 |
| Gene: | 3D (Human poliovirus 1 Mahoney) |
| Activity: | RNA-directed RNA polymerase, with EC number 2.7.7.48 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum |
Function
[POLG_POL1M] Capsid proteins VP1, VP2, VP3 and VP4 form a closed capsid enclosing the viral positive strand RNA genome. VP4 lies on the inner surface of the protein shell formed by VP1, VP2 and VP3. All the three latter proteins contain a beta-sheet structure called beta-barrel jelly roll. Together they form an icosahedral capsid (T=3) composed of 60 copies of each VP1, VP2, and VP3, with a diameter of approximately 300 Angstroms. VP1 is situated at the 12 fivefold axes, whereas VP2 and VP3 are located at the quasi-sixfold axes. The interaction of five VP1 proteins in the fivefold axes results in a prominent protusion extending to about 25 Angstroms from the capsid shell. The resulting structure appears as a steep plateau encircled by a valley or cleft. This depression also termed canyon is the receptor binding site. The capsid interacts with human PVR at this site to provide virion attachment to target cell. This attachment induces virion internalization predominantly through clathrin- and caveolin-independent endocytosis in Hela cells and through caveolin-mediated endocytosis in brain microvascular endothelial cells. VP4 and VP1 subsequently undergo conformational changes leading to the formation of a pore in the endosomal membrane, thereby delivering the viral genome into the cytoplasm.[1] [2] [3] VP0 precursor is a component of immature procapsids (By similarity).[4] [5] [6] Protein 2A is a cysteine protease that is responsible for the cleavage between the P1 and P2 regions. It cleaves the host translation initiation factor EIF4G1, in order to shut down the capped cellular mRNA transcription.[7] [8] [9] Protein 2B affects membrane integrity and cause an increase in membrane permeability (By similarity).[10] [11] [12] Protein 2C associates with and induces structural rearrangements of intracellular membranes. It displays RNA-binding, nucleotide binding and NTPase activities.[13] [14] [15] Protein 3A, via its hydrophobic domain, serves as membrane anchor. It also inhibits endoplasmic reticulum-to-Golgi transport (By similarity).[16] [17] [18] Protein 3C is a cysteine protease that generates mature viral proteins from the precursor polyprotein. In addition to its proteolytic activity, it binds to viral RNA, and thus influences viral genome replication. RNA and substrate bind co-operatively to the protease (By similarity).[19] [20] [21] RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals (By similarity).[22] [23] [24]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The viral RNA-dependent RNA polymerases show a conserved structure where the fingers domain interacts with the top of the thumb domain to create a tunnel through which nucleotide triphosphates reach the active site. We have solved the crystal structures of poliovirus polymerase (3D(pol)) in complex with all four NTPs, showing that they all bind in a common pre-insertion site where the phosphate groups are not yet positioned over the active site. The NTPs interact with both the fingers and palm domains, forming bridging interactions that explain the increased thermal stability of 3D(pol) in the presence of NTPs. We have also examined the importance of the fingers-thumb domain interaction for the function and structural stability of 3D(pol). Results from thermal denaturation experiments using circular dichroism and 2-anilino-6-napthaline-sulfonate (ANS) fluorescence show that 3D(pol) has a melting temperature of only approximately 40 degrees C. NTP binding stabilizes the protein and increases the melting by 5-6 degrees C while mutations in the fingers-thumb domain interface destabilize the protein and reduce the melting point by as much as 6 degrees C. In particular, the burial of Phe30 and Phe34 from the tip of the index finger into a pocket at the top of the thumb and the presence of Trp403 on the thumb domain are key interactions required to maintain the structural integrity of the polymerase. The data suggest the fingers domain has significant conformational flexibility and exists in a highly dynamic molten globule state at physiological temperature. The role of the enclosed active site motif as a structural scaffold for constraining the fingers domain and accommodating conformational changes in 3D(pol) and other viral polymerases during the catalytic cycle is discussed.
Stabilization of poliovirus polymerase by NTP binding and fingers-thumb interactions.,Thompson AA, Albertini RA, Peersen OB J Mol Biol. 2007 Mar 9;366(5):1459-74. Epub 2006 Dec 1. PMID:17223130[25]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ventoso I, MacMillan SE, Hershey JW, Carrasco L. Poliovirus 2A proteinase cleaves directly the eIF-4G subunit of eIF-4F complex. FEBS Lett. 1998 Sep 11;435(1):79-83. PMID:9755863
- ↑ Bubeck D, Filman DJ, Cheng N, Steven AC, Hogle JM, Belnap DM. The structure of the poliovirus 135S cell entry intermediate at 10-angstrom resolution reveals the location of an externalized polypeptide that binds to membranes. J Virol. 2005 Jun;79(12):7745-55. PMID:15919927 doi:79/12/7745
- ↑ Bergelson JM. New (fluorescent) light on poliovirus entry. Trends Microbiol. 2008 Feb;16(2):44-7. doi: 10.1016/j.tim.2007.12.004. Epub 2008 , Jan 10. PMID:18191571 doi:10.1016/j.tim.2007.12.004
- ↑ Ventoso I, MacMillan SE, Hershey JW, Carrasco L. Poliovirus 2A proteinase cleaves directly the eIF-4G subunit of eIF-4F complex. FEBS Lett. 1998 Sep 11;435(1):79-83. PMID:9755863
- ↑ Bubeck D, Filman DJ, Cheng N, Steven AC, Hogle JM, Belnap DM. The structure of the poliovirus 135S cell entry intermediate at 10-angstrom resolution reveals the location of an externalized polypeptide that binds to membranes. J Virol. 2005 Jun;79(12):7745-55. PMID:15919927 doi:79/12/7745
- ↑ Bergelson JM. New (fluorescent) light on poliovirus entry. Trends Microbiol. 2008 Feb;16(2):44-7. doi: 10.1016/j.tim.2007.12.004. Epub 2008 , Jan 10. PMID:18191571 doi:10.1016/j.tim.2007.12.004
- ↑ Ventoso I, MacMillan SE, Hershey JW, Carrasco L. Poliovirus 2A proteinase cleaves directly the eIF-4G subunit of eIF-4F complex. FEBS Lett. 1998 Sep 11;435(1):79-83. PMID:9755863
- ↑ Bubeck D, Filman DJ, Cheng N, Steven AC, Hogle JM, Belnap DM. The structure of the poliovirus 135S cell entry intermediate at 10-angstrom resolution reveals the location of an externalized polypeptide that binds to membranes. J Virol. 2005 Jun;79(12):7745-55. PMID:15919927 doi:79/12/7745
- ↑ Bergelson JM. New (fluorescent) light on poliovirus entry. Trends Microbiol. 2008 Feb;16(2):44-7. doi: 10.1016/j.tim.2007.12.004. Epub 2008 , Jan 10. PMID:18191571 doi:10.1016/j.tim.2007.12.004
- ↑ Ventoso I, MacMillan SE, Hershey JW, Carrasco L. Poliovirus 2A proteinase cleaves directly the eIF-4G subunit of eIF-4F complex. FEBS Lett. 1998 Sep 11;435(1):79-83. PMID:9755863
- ↑ Bubeck D, Filman DJ, Cheng N, Steven AC, Hogle JM, Belnap DM. The structure of the poliovirus 135S cell entry intermediate at 10-angstrom resolution reveals the location of an externalized polypeptide that binds to membranes. J Virol. 2005 Jun;79(12):7745-55. PMID:15919927 doi:79/12/7745
- ↑ Bergelson JM. New (fluorescent) light on poliovirus entry. Trends Microbiol. 2008 Feb;16(2):44-7. doi: 10.1016/j.tim.2007.12.004. Epub 2008 , Jan 10. PMID:18191571 doi:10.1016/j.tim.2007.12.004
- ↑ Ventoso I, MacMillan SE, Hershey JW, Carrasco L. Poliovirus 2A proteinase cleaves directly the eIF-4G subunit of eIF-4F complex. FEBS Lett. 1998 Sep 11;435(1):79-83. PMID:9755863
- ↑ Bubeck D, Filman DJ, Cheng N, Steven AC, Hogle JM, Belnap DM. The structure of the poliovirus 135S cell entry intermediate at 10-angstrom resolution reveals the location of an externalized polypeptide that binds to membranes. J Virol. 2005 Jun;79(12):7745-55. PMID:15919927 doi:79/12/7745
- ↑ Bergelson JM. New (fluorescent) light on poliovirus entry. Trends Microbiol. 2008 Feb;16(2):44-7. doi: 10.1016/j.tim.2007.12.004. Epub 2008 , Jan 10. PMID:18191571 doi:10.1016/j.tim.2007.12.004
- ↑ Ventoso I, MacMillan SE, Hershey JW, Carrasco L. Poliovirus 2A proteinase cleaves directly the eIF-4G subunit of eIF-4F complex. FEBS Lett. 1998 Sep 11;435(1):79-83. PMID:9755863
- ↑ Bubeck D, Filman DJ, Cheng N, Steven AC, Hogle JM, Belnap DM. The structure of the poliovirus 135S cell entry intermediate at 10-angstrom resolution reveals the location of an externalized polypeptide that binds to membranes. J Virol. 2005 Jun;79(12):7745-55. PMID:15919927 doi:79/12/7745
- ↑ Bergelson JM. New (fluorescent) light on poliovirus entry. Trends Microbiol. 2008 Feb;16(2):44-7. doi: 10.1016/j.tim.2007.12.004. Epub 2008 , Jan 10. PMID:18191571 doi:10.1016/j.tim.2007.12.004
- ↑ Ventoso I, MacMillan SE, Hershey JW, Carrasco L. Poliovirus 2A proteinase cleaves directly the eIF-4G subunit of eIF-4F complex. FEBS Lett. 1998 Sep 11;435(1):79-83. PMID:9755863
- ↑ Bubeck D, Filman DJ, Cheng N, Steven AC, Hogle JM, Belnap DM. The structure of the poliovirus 135S cell entry intermediate at 10-angstrom resolution reveals the location of an externalized polypeptide that binds to membranes. J Virol. 2005 Jun;79(12):7745-55. PMID:15919927 doi:79/12/7745
- ↑ Bergelson JM. New (fluorescent) light on poliovirus entry. Trends Microbiol. 2008 Feb;16(2):44-7. doi: 10.1016/j.tim.2007.12.004. Epub 2008 , Jan 10. PMID:18191571 doi:10.1016/j.tim.2007.12.004
- ↑ Ventoso I, MacMillan SE, Hershey JW, Carrasco L. Poliovirus 2A proteinase cleaves directly the eIF-4G subunit of eIF-4F complex. FEBS Lett. 1998 Sep 11;435(1):79-83. PMID:9755863
- ↑ Bubeck D, Filman DJ, Cheng N, Steven AC, Hogle JM, Belnap DM. The structure of the poliovirus 135S cell entry intermediate at 10-angstrom resolution reveals the location of an externalized polypeptide that binds to membranes. J Virol. 2005 Jun;79(12):7745-55. PMID:15919927 doi:79/12/7745
- ↑ Bergelson JM. New (fluorescent) light on poliovirus entry. Trends Microbiol. 2008 Feb;16(2):44-7. doi: 10.1016/j.tim.2007.12.004. Epub 2008 , Jan 10. PMID:18191571 doi:10.1016/j.tim.2007.12.004
- ↑ Thompson AA, Albertini RA, Peersen OB. Stabilization of poliovirus polymerase by NTP binding and fingers-thumb interactions. J Mol Biol. 2007 Mar 9;366(5):1459-74. Epub 2006 Dec 1. PMID:17223130 doi:http://dx.doi.org/10.1016/j.jmb.2006.11.070
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