2hw3: Difference between revisions

Revision as of 06:47, 4 May 2008

T:O6-methyl-guanine pair in the polymerase postinsertion site (-1 basepair position)

OverviewOverview

Methylating agents are widespread environmental carcinogens that generate a broad spectrum of DNA damage. Methylation at the guanine O(6) position confers the greatest mutagenic and carcinogenic potential. DNA polymerases insert cytosine and thymine with similar efficiency opposite O(6)-methyl-guanine (O6MeG). We combined pre-steady-state kinetic analysis and a series of nine x-ray crystal structures to contrast the reaction pathways of accurate and mutagenic replication of O6MeG in a high-fidelity DNA polymerase from Bacillus stearothermophilus. Polymerases achieve substrate specificity by selecting for nucleotides with shape and hydrogen-bonding patterns that complement a canonical DNA template. Our structures reveal that both thymine and cytosine O6MeG base pairs evade proofreading by mimicking the essential molecular features of canonical substrates. The steric mimicry depends on stabilization of a rare cytosine tautomer in C.O6MeG-polymerase complexes. An unusual electrostatic interaction between O-methyl protons and a thymine carbonyl oxygen helps stabilize T.O6MeG pairs bound to DNA polymerase. Because DNA methylators constitute an important class of chemotherapeutic agents, the molecular mechanisms of replication of these DNA lesions are important for our understanding of both the genesis and treatment of cancer.

About this StructureAbout this Structure

2HW3 is a Single protein structure of sequence from Geobacillus stearothermophilus. Full crystallographic information is available from OCA.

ReferenceReference

The structural basis for the mutagenicity of O(6)-methyl-guanine lesions., Warren JJ, Forsberg LJ, Beese LS, Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19701-6. Epub 2006 Dec 18. PMID:17179038 Page seeded by OCA on Sun May 4 06:47:00 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
 [[Image:2hw3.gif|left|200px]]
- {{Structure
+<!--
-|PDB= 2hw3 |SIZE=350|CAPTION= <scene name='initialview01'>2hw3</scene>, resolution 1.980&Aring;
+The line below this paragraph, containing "STRUCTURE_2hw3", creates the "Structure Box" on the page.
-|SITE=
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=6OG:6-O-METHYL+GUANOSINE-5&#39;-MONOPHOSPHATE'>6OG</scene>, <scene name='pdbligand=DA:2&#39;-DEOXYADENOSINE-5&#39;-MONOPHOSPHATE'>DA</scene>, <scene name='pdbligand=DC:2&#39;-DEOXYCYTIDINE-5&#39;-MONOPHOSPHATE'>DC</scene>, <scene name='pdbligand=DG:2&#39;-DEOXYGUANOSINE-5&#39;-MONOPHOSPHATE'>DG</scene>, <scene name='pdbligand=DT:THYMIDINE-5&#39;-MONOPHOSPHATE'>DT</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SUC:SUCROSE'>SUC</scene>
+or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/DNA-directed_DNA_polymerase DNA-directed DNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.7 2.7.7.7] </span>
+or leave the SCENE parameter empty for the default display.
-|GENE= polA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1422 Geobacillus stearothermophilus])
+-->
-|DOMAIN=
+{{STRUCTURE_2hw3|  PDB=2hw3  |  SCENE=  }}
-|RELATEDENTRY=[[2hhw|2HHW]], [[2hhv|2HHV]], [[2hhu|2HHU]], [[2hht|2HHT]], [[2hhs|2HHS]], [[2hhx|2HHX]], [[2hhy|2HHY]], [[2hhq|2HHQ]], [[2hvh|2HVH]], [[2hvi|2HVI]]
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2hw3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2hw3 OCA], [http://www.ebi.ac.uk/pdbsum/2hw3 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2hw3 RCSB]</span>
-}}
 '''T:O6-methyl-guanine pair in the polymerase postinsertion site (-1 basepair position)'''
@@ Line 29: / Line 26: @@
 [[Category: Forsberg, L J.]]
 [[Category: Warren, J J.]]
-[[Category: dna polymerase i]]
+[[Category: Dna polymerase i]]
-[[Category: dna replication]]
+[[Category: Dna replication]]
-[[Category: klenow fragment]]
+[[Category: Klenow fragment]]
-[[Category: o6-methyl-guanine]]
+[[Category: O6-methyl-guanine]]
-[[Category: protein-dna complex]]
+[[Category: Protein-dna complex]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 06:47:00 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:36:14 2008''