2ic3

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Line 1: Line 1:
-
[[Image:2ic3.gif|left|200px]]
+
{{Seed}}
 +
[[Image:2ic3.png|left|200px]]
<!--
<!--
Line 9: Line 10:
{{STRUCTURE_2ic3| PDB=2ic3 | SCENE= }}
{{STRUCTURE_2ic3| PDB=2ic3 | SCENE= }}
-
'''Crystal Structure of K103N/Y181C Mutant HIV-1 Reverse Transcriptase (RT) in Complex with Nonnucleoside Inhibitor HBY 097'''
+
===Crystal Structure of K103N/Y181C Mutant HIV-1 Reverse Transcriptase (RT) in Complex with Nonnucleoside Inhibitor HBY 097===
-
==Overview==
+
<!--
-
Lys103Asn and Tyr181Cys are the two mutations frequently observed in patients exposed to various non-nucleoside reverse transcriptase inhibitor drugs (NNRTIs). Human immunodeficiency virus (HIV) strains containing both reverse transcriptase (RT) mutations are resistant to all of the approved NNRTI drugs. We have determined crystal structures of Lys103Asn/Tyr181Cys mutant HIV-1 RT with and without a bound non-nucleoside inhibitor (HBY 097, (S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthio-methyl)-3,4-dihydroquinox alin-2(1H)-thione) at 3.0 A and 2.5 A resolution, respectively. The structure of the double mutant RT/HBY 097 complex shows a rearrangement of the isopropoxycarbonyl group of HBY 097 compared to its binding with wild-type RT. HBY 097 makes a hydrogen bond with the thiol group of Cys181 that helps the drug retain potency against the Tyr181Cys mutation. The structure of the unliganded double mutant HIV-1 RT showed that Lys103Asn mutation facilitates coordination of a sodium ion with Lys101 O, Asn103 N and O(delta1), Tyr188 O(eta), and two water molecules. The formation of the binding pocket requires the removal of the sodium ion. Although the RT alone and the RT/HBY 097 complex were crystallized in the presence of ATP, only the RT has an ATP coordinated with two Mn(2+) at the polymerase active site. The metal coordination mimics a reaction intermediate state in which complete octahedral coordination was observed for both metal ions. Asp186 coordinates at an axial position whereas the carboxylates of Asp110 and Asp185 are in the planes of coordination of both metal ions. The structures provide evidence that NNRTIs restrict the flexibility of the YMDD loop and prevent the catalytic aspartate residues from adopting their metal-binding conformations.
+
The line below this paragraph, {{ABSTRACT_PUBMED_17056061}}, adds the Publication Abstract to the page
 +
(as it appears on PubMed at http://www.pubmed.gov), where 17056061 is the PubMed ID number.
 +
-->
 +
{{ABSTRACT_PUBMED_17056061}}
==About this Structure==
==About this Structure==
Line 20: Line 24:
==Reference==
==Reference==
Crystal structures of clinically relevant Lys103Asn/Tyr181Cys double mutant HIV-1 reverse transcriptase in complexes with ATP and non-nucleoside inhibitor HBY 097., Das K, Sarafianos SG, Clark AD Jr, Boyer PL, Hughes SH, Arnold E, J Mol Biol. 2007 Jan 5;365(1):77-89. Epub 2006 Sep 15. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17056061 17056061]
Crystal structures of clinically relevant Lys103Asn/Tyr181Cys double mutant HIV-1 reverse transcriptase in complexes with ATP and non-nucleoside inhibitor HBY 097., Das K, Sarafianos SG, Clark AD Jr, Boyer PL, Hughes SH, Arnold E, J Mol Biol. 2007 Jan 5;365(1):77-89. Epub 2006 Sep 15. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17056061 17056061]
 +
 +
Structure of unliganded HIV-1 reverse transcriptase at 2.7 A resolution: implications of conformational changes for polymerization and inhibition mechanisms., Hsiou Y, Ding J, Das K, Clark AD Jr, Hughes SH, Arnold E, Structure. 1996 Jul 15;4(7):853-60. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/8805568 8805568]
 +
 +
Crystal structures of 8-Cl and 9-Cl TIBO complexed with wild-type HIV-1 RT and 8-Cl TIBO complexed with the Tyr181Cys HIV-1 RT drug-resistant mutant., Das K, Ding J, Hsiou Y, Clark AD Jr, Moereels H, Koymans L, Andries K, Pauwels R, Janssen PA, Boyer PL, Clark P, Smith RH Jr, Kroeger Smith MB, Michejda CJ, Hughes SH, Arnold E, J Mol Biol. 1996 Dec 20;264(5):1085-100. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/9000632 9000632]
 +
 +
Structures of Tyr188Leu mutant and wild-type HIV-1 reverse transcriptase complexed with the non-nucleoside inhibitor HBY 097: inhibitor flexibility is a useful design feature for reducing drug resistance., Hsiou Y, Das K, Ding J, Clark AD Jr, Kleim JP, Rosner M, Winkler I, Riess G, Hughes SH, Arnold E, J Mol Biol. 1998 Nov 27;284(2):313-23. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/9813120 9813120]
 +
 +
The Lys103Asn mutation of HIV-1 RT: a novel mechanism of drug resistance., Hsiou Y, Ding J, Das K, Clark AD Jr, Boyer PL, Lewi P, Janssen PA, Kleim JP, Rosner M, Hughes SH, Arnold E, J Mol Biol. 2001 Jun 1;309(2):437-45. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/11371163 11371163]
 +
 +
Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants., Das K, Clark AD Jr, Lewi PJ, Heeres J, De Jonge MR, Koymans LM, Vinkers HM, Daeyaert F, Ludovici DW, Kukla MJ, De Corte B, Kavash RW, Ho CY, Ye H, Lichtenstein MA, Andries K, Pauwels R, De Bethune MP, Boyer PL, Clark P, Hughes SH, Janssen PA, Arnold E, J Med Chem. 2004 May 6;47(10):2550-60. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15115397 15115397]
[[Category: Human immunodeficiency virus 1]]
[[Category: Human immunodeficiency virus 1]]
[[Category: Protein complex]]
[[Category: Protein complex]]
Line 32: Line 46:
[[Category: Nonnucleoside inhibitor]]
[[Category: Nonnucleoside inhibitor]]
[[Category: Rt]]
[[Category: Rt]]
-
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 07:19:02 2008''
+
 
 +
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 03:30:03 2008''

Revision as of 00:30, 29 July 2008

Image:2ic3.png

Template:STRUCTURE 2ic3

Crystal Structure of K103N/Y181C Mutant HIV-1 Reverse Transcriptase (RT) in Complex with Nonnucleoside Inhibitor HBY 097

Template:ABSTRACT PUBMED 17056061

About this Structure

2IC3 is a Protein complex structure of sequences from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.

Reference

Crystal structures of clinically relevant Lys103Asn/Tyr181Cys double mutant HIV-1 reverse transcriptase in complexes with ATP and non-nucleoside inhibitor HBY 097., Das K, Sarafianos SG, Clark AD Jr, Boyer PL, Hughes SH, Arnold E, J Mol Biol. 2007 Jan 5;365(1):77-89. Epub 2006 Sep 15. PMID:17056061

Structure of unliganded HIV-1 reverse transcriptase at 2.7 A resolution: implications of conformational changes for polymerization and inhibition mechanisms., Hsiou Y, Ding J, Das K, Clark AD Jr, Hughes SH, Arnold E, Structure. 1996 Jul 15;4(7):853-60. PMID:8805568

Crystal structures of 8-Cl and 9-Cl TIBO complexed with wild-type HIV-1 RT and 8-Cl TIBO complexed with the Tyr181Cys HIV-1 RT drug-resistant mutant., Das K, Ding J, Hsiou Y, Clark AD Jr, Moereels H, Koymans L, Andries K, Pauwels R, Janssen PA, Boyer PL, Clark P, Smith RH Jr, Kroeger Smith MB, Michejda CJ, Hughes SH, Arnold E, J Mol Biol. 1996 Dec 20;264(5):1085-100. PMID:9000632

Structures of Tyr188Leu mutant and wild-type HIV-1 reverse transcriptase complexed with the non-nucleoside inhibitor HBY 097: inhibitor flexibility is a useful design feature for reducing drug resistance., Hsiou Y, Das K, Ding J, Clark AD Jr, Kleim JP, Rosner M, Winkler I, Riess G, Hughes SH, Arnold E, J Mol Biol. 1998 Nov 27;284(2):313-23. PMID:9813120

The Lys103Asn mutation of HIV-1 RT: a novel mechanism of drug resistance., Hsiou Y, Ding J, Das K, Clark AD Jr, Boyer PL, Lewi P, Janssen PA, Kleim JP, Rosner M, Hughes SH, Arnold E, J Mol Biol. 2001 Jun 1;309(2):437-45. PMID:11371163

Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants., Das K, Clark AD Jr, Lewi PJ, Heeres J, De Jonge MR, Koymans LM, Vinkers HM, Daeyaert F, Ludovici DW, Kukla MJ, De Corte B, Kavash RW, Ho CY, Ye H, Lichtenstein MA, Andries K, Pauwels R, De Bethune MP, Boyer PL, Clark P, Hughes SH, Janssen PA, Arnold E, J Med Chem. 2004 May 6;47(10):2550-60. PMID:15115397

Page seeded by OCA on Tue Jul 29 03:30:03 2008

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2ic3"
Personal tools