1c1b: Difference between revisions

Revision as of 13:01, 21 February 2008

CRYSTAL STRUCTURE OF HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH GCA-186

OverviewOverview

Two analogues of the nonnucleoside inhibitor of HIV-1 RT, MKC-442 (emivirine), containing different C6 substituents have been designed to be less susceptible to the commonly found drug-resistance mutation of Tyr181Cys. Compound TNK-6123 had a C6 thiocyclohexyl group designed to have more flexibility in adapting to the mutated drug-binding site. GCA-186 had additional 3',5'-dimethyl substituents aimed at forming close contacts with the conserved residue Trp229. Both compounds showed approximately 30-fold greater inhibitory effect than MKC-442 to the Tyr181Cys mutant virus as well as to the clinically important Lys103Asn virus. X-ray crystallographic structure determination of complexes with HIV-1 RT confirmed the predicted binding modes. These strategies might be used to improve the resilience of other NNRTI series against common drug-resistance mutations.

About this StructureAbout this Structure

1C1B is a Protein complex structure of sequences from Human immunodeficiency virus 1 with as ligand. Active as RNA-directed DNA polymerase, with EC number 2.7.7.49 Full crystallographic information is available from OCA.

ReferenceReference

Design of MKC-442 (emivirine) analogues with improved activity against drug-resistant HIV mutants., Hopkins AL, Ren J, Tanaka H, Baba M, Okamato M, Stuart DI, Stammers DK, J Med Chem. 1999 Nov 4;42(22):4500-5. PMID:10579814

Page seeded by OCA on Thu Feb 21 12:01:20 2008

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OCA

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-[[Image:1c1b.gif|left|200px]]<br />
+[[Image:1c1b.gif|left|200px]]<br /><applet load="1c1b" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="1c1b" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="1c1b, resolution 2.5&Aring;" />
 '''CRYSTAL STRUCTURE OF HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH GCA-186'''<br />
 ==Overview==
-Two analogues of the nonnucleoside inhibitor of HIV-1 RT, MKC-442, (emivirine), containing different C6 substituents have been designed to be, less susceptible to the commonly found drug-resistance mutation of, Tyr181Cys. Compound TNK-6123 had a C6 thiocyclohexyl group designed to, have more flexibility in adapting to the mutated drug-binding site., GCA-186 had additional 3',5'-dimethyl substituents aimed at forming close, contacts with the conserved residue Trp229. Both compounds showed, approximately 30-fold greater inhibitory effect than MKC-442 to the, Tyr181Cys mutant virus as well as to the clinically important Lys103Asn, virus. X-ray crystallographic structure determination of complexes with, HIV-1 RT confirmed the predicted binding modes. These strategies might be, used to improve the resilience of other NNRTI series against common, drug-resistance mutations.
+Two analogues of the nonnucleoside inhibitor of HIV-1 RT, MKC-442 (emivirine), containing different C6 substituents have been designed to be less susceptible to the commonly found drug-resistance mutation of Tyr181Cys. Compound TNK-6123 had a C6 thiocyclohexyl group designed to have more flexibility in adapting to the mutated drug-binding site. GCA-186 had additional 3',5'-dimethyl substituents aimed at forming close contacts with the conserved residue Trp229. Both compounds showed approximately 30-fold greater inhibitory effect than MKC-442 to the Tyr181Cys mutant virus as well as to the clinically important Lys103Asn virus. X-ray crystallographic structure determination of complexes with HIV-1 RT confirmed the predicted binding modes. These strategies might be used to improve the resilience of other NNRTI series against common drug-resistance mutations.
 ==About this Structure==
-C1B is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1] with GCA as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/RNA-directed_DNA_polymerase RNA-directed DNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.49 2.7.7.49] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1C1B OCA].
+C1B is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1] with <scene name='pdbligand=GCA:'>GCA</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/RNA-directed_DNA_polymerase RNA-directed DNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.49 2.7.7.49] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1C1B OCA].
 ==Reference==
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 [[Category: RNA-directed DNA polymerase]]
 [[Category: Baba, B.]]
-[[Category: Hopkins, A.L.]]
+[[Category: Hopkins, A L.]]
 [[Category: Okamato, M.]]
 [[Category: Ren, J.]]
-[[Category: Stammers, D.K.]]
+[[Category: Stammers, D K.]]
-[[Category: Stuart, D.I.]]
+[[Category: Stuart, D I.]]
 [[Category: Tanaka, H.]]
 [[Category: GCA]]
@@ Line 29: / Line 28: @@
 [[Category: transferase]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Thu Nov  8 13:55:47 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:01:20 2008''