3v4k

From Proteopedia

(Difference between revisions)

Revision as of 11:45, 25 December 2014

First-In-Class Small Molecule Inhibitors of the Single-strand DNA Cytosine Deaminase APOBEC3G

Structural highlights

3v4k is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	3v4j
Gene:	APOBEC3G, MDS019 (Homo sapiens)
Resources:	FirstGlance, OCA, RCSB, PDBsum

Function

[ABC3G_HUMAN] DNA deaminase (cytidine deaminase) that mediates a form of innate resistance to retroviral infections (at least to HIV-1 infection) by triggering G-to-A hypermutation in the newly synthesized viral DNA. The replacements C-to-U in the minus strand DNA of HIV-1 during reverse transcription, leads to G-to-A transitions in the plus strand. The inhibition of viral replication is either due to the degradation of the minus strand before its integration or to the lethality of the hypermutations. Modification of both DNA strands is not excluded. This antiviral activity is neutralized by the virion infectivity factor (VIF), that prevents the incorporation of APOBEC3G into progeny HIV-1 virions by both inhibiting its translation and/or by inducing its ubiquitination and subsequent degradation by the 26S proteasome. May also prevent the transposition of a subset of retroelements. Binds a variety of RNAs, but does not display detectable APOB, NF1 and NAT1 mRNA editing.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11] ^[12]

Publication Abstract from PubMed

APOBEC3G is a single-stranded DNA cytosine deaminase that comprises part of the innate immune response to viruses and transposons. Although APOBEC3G is the prototype for understanding the larger mammalian polynucleotide deaminase family, no specific chemical inhibitors exist to modulate its activity. High-throughput screening identified 34 compounds that inhibit APOBEC3G catalytic activity. Twenty of 34 small molecules contained catechol moieties, which are known to be sulfhydryl reactive following oxidation to the orthoquinone. Located proximal to the active site, C321 was identified as the binding site for the inhibitors by a combination of mutational screening, structural analysis, and mass spectrometry. Bulkier substitutions C321-to-L, F, Y, or W mimicked chemical inhibition. A strong specificity for APOBEC3G was evident, as most compounds failed to inhibit the related APOBEC3A enzyme or the unrelated enzymes E. coli uracil DNA glycosylase, HIV-1 RNase H, or HIV-1 integrase. Partial, but not complete, sensitivity could be conferred to APOBEC3A by introducing the entire C321 loop from APOBEC3G. Thus, a structural model is presented in which the mechanism of inhibition is both specific and competitive, by binding a pocket adjacent to the APOBEC3G active site, reacting with C321, and blocking access to substrate DNA cytosines.

First-In-Class Small Molecule Inhibitors of the Single-Strand DNA Cytosine Deaminase APOBEC3G.,Li M, Shandilya SM, Carpenter MA, Rathore A, Brown WL, Perkins AL, Harki DA, Solberg J, Hook DJ, Pandey KK, Parniak MA, Johnson JR, Krogan NJ, Somasundaran M, Ali A, Schiffer CA, Harris RS ACS Chem Biol. 2012 Jan 17. PMID:22181350^[13]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Kao S, Khan MA, Miyagi E, Plishka R, Buckler-White A, Strebel K. The human immunodeficiency virus type 1 Vif protein reduces intracellular expression and inhibits packaging of APOBEC3G (CEM15), a cellular inhibitor of virus infectivity. J Virol. 2003 Nov;77(21):11398-407. PMID:14557625
↑ Sheehy AM, Gaddis NC, Choi JD, Malim MH. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature. 2002 Aug 8;418(6898):646-50. Epub 2002 Jul 14. PMID:12167863 doi:10.1038/nature00939
↑ Mangeat B, Turelli P, Caron G, Friedli M, Perrin L, Trono D. Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts. Nature. 2003 Jul 3;424(6944):99-103. Epub 2003 May 28. PMID:12808466 doi:10.1038/nature01709
↑ Harris RS, Bishop KN, Sheehy AM, Craig HM, Petersen-Mahrt SK, Watt IN, Neuberger MS, Malim MH. DNA deamination mediates innate immunity to retroviral infection. Cell. 2003 Jun 13;113(6):803-9. PMID:12809610
↑ Zhang H, Yang B, Pomerantz RJ, Zhang C, Arunachalam SC, Gao L. The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA. Nature. 2003 Jul 3;424(6944):94-8. Epub 2003 May 28. PMID:12808465 doi:10.1038/nature01707
↑ Mariani R, Chen D, Schrofelbauer B, Navarro F, Konig R, Bollman B, Munk C, Nymark-McMahon H, Landau NR. Species-specific exclusion of APOBEC3G from HIV-1 virions by Vif. Cell. 2003 Jul 11;114(1):21-31. PMID:12859895
↑ Shindo K, Takaori-Kondo A, Kobayashi M, Abudu A, Fukunaga K, Uchiyama T. The enzymatic activity of CEM15/Apobec-3G is essential for the regulation of the infectivity of HIV-1 virion but not a sole determinant of its antiviral activity. J Biol Chem. 2003 Nov 7;278(45):44412-6. Epub 2003 Sep 11. PMID:12970355 doi:http://dx.doi.org/10.1074/jbc.C300376200
↑ Sheehy AM, Gaddis NC, Malim MH. The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 Vif. Nat Med. 2003 Nov;9(11):1404-7. Epub 2003 Oct 5. PMID:14528300 doi:10.1038/nm945
↑ Turelli P, Mangeat B, Jost S, Vianin S, Trono D. Inhibition of hepatitis B virus replication by APOBEC3G. Science. 2004 Mar 19;303(5665):1829. PMID:15031497 doi:10.1126/science.1092066
↑ Chen H, Lilley CE, Yu Q, Lee DV, Chou J, Narvaiza I, Landau NR, Weitzman MD. APOBEC3A is a potent inhibitor of adeno-associated virus and retrotransposons. Curr Biol. 2006 Mar 7;16(5):480-5. PMID:16527742 doi:10.1016/j.cub.2006.01.031
↑ Bulliard Y, Narvaiza I, Bertero A, Peddi S, Rohrig UF, Ortiz M, Zoete V, Castro-Diaz N, Turelli P, Telenti A, Michielin O, Weitzman MD, Trono D. Structure-function analyses point to a polynucleotide-accommodating groove essential for APOBEC3A restriction activities. J Virol. 2011 Feb;85(4):1765-76. doi: 10.1128/JVI.01651-10. Epub 2010 Dec 1. PMID:21123384 doi:10.1128/JVI.01651-10
↑ Chen KM, Harjes E, Gross PJ, Fahmy A, Lu Y, Shindo K, Harris RS, Matsuo H. Structure of the DNA deaminase domain of the HIV-1 restriction factor APOBEC3G. Nature. 2008 Mar 6;452(7183):116-9. Epub 2008 Feb 20. PMID:18288108 doi:10.1038/nature06638
↑ Li M, Shandilya SM, Carpenter MA, Rathore A, Brown WL, Perkins AL, Harki DA, Solberg J, Hook DJ, Pandey KK, Parniak MA, Johnson JR, Krogan NJ, Somasundaran M, Ali A, Schiffer CA, Harris RS. First-In-Class Small Molecule Inhibitors of the Single-Strand DNA Cytosine Deaminase APOBEC3G. ACS Chem Biol. 2012 Jan 17. PMID:22181350 doi:10.1021/cb200440y

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3v4k"

@@ Line 3: / Line 3: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[3v4k]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3V4K OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3V4K FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene><br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3v4j|3v4j]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3v4j|3v4j]]</td></tr>
-<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">APOBEC3G, MDS019 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">APOBEC3G, MDS019 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
-<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3v4k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3v4k OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3v4k RCSB], [http://www.ebi.ac.uk/pdbsum/3v4k PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3v4k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3v4k OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3v4k RCSB], [http://www.ebi.ac.uk/pdbsum/3v4k PDBsum]</span></td></tr>
-<table>
+</table>
+== Function ==
+[[http://www.uniprot.org/uniprot/ABC3G_HUMAN ABC3G_HUMAN]] DNA deaminase (cytidine deaminase) that mediates a form of innate resistance to retroviral infections (at least to HIV-1 infection) by triggering G-to-A hypermutation in the newly synthesized viral DNA. The replacements C-to-U in the minus strand DNA of HIV-1 during reverse transcription, leads to G-to-A transitions in the plus strand. The inhibition of viral replication is either due to the degradation of the minus strand before its integration or to the lethality of the hypermutations. Modification of both DNA strands is not excluded. This antiviral activity is neutralized by the virion infectivity factor (VIF), that prevents the incorporation of APOBEC3G into progeny HIV-1 virions by both inhibiting its translation and/or by inducing its ubiquitination and subsequent degradation by the 26S proteasome. May also prevent the transposition of a subset of retroelements. Binds a variety of RNAs, but does not display detectable APOB, NF1 and NAT1 mRNA editing.<ref>PMID:14557625</ref> <ref>PMID:12167863</ref> <ref>PMID:12808466</ref> <ref>PMID:12809610</ref> <ref>PMID:12808465</ref> <ref>PMID:12859895</ref> <ref>PMID:12970355</ref> <ref>PMID:14528300</ref> <ref>PMID:15031497</ref> <ref>PMID:16527742</ref> <ref>PMID:21123384</ref> <ref>PMID:18288108</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 14: / Line 16: @@
 First-In-Class Small Molecule Inhibitors of the Single-Strand DNA Cytosine Deaminase APOBEC3G.,Li M, Shandilya SM, Carpenter MA, Rathore A, Brown WL, Perkins AL, Harki DA, Solberg J, Hook DJ, Pandey KK, Parniak MA, Johnson JR, Krogan NJ, Somasundaran M, Ali A, Schiffer CA, Harris RS ACS Chem Biol. 2012 Jan 17. PMID:22181350<ref>PMID:22181350</ref>
-From MEDLINEÂ®/PubMedÂ®, a database of the U.S. National Library of Medicine.<br>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
 == References ==
@@ Line 21: / Line 23: @@
 </StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Ali, A.]]
+[[Category: Ali, A]]
-[[Category: Schiffer, C A.]]
+[[Category: Schiffer, C A]]
-[[Category: Shandilya, S M.D.]]
+[[Category: Shandilya, S M.D]]
 [[Category: Antiviral defense]]
 [[Category: Apobec3g]]

3v4k

From Proteopedia

Revision as of 11:45, 25 December 2014

First-In-Class Small Molecule Inhibitors of the Single-strand DNA Cytosine Deaminase APOBEC3G

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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