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1ikw

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[[Image:1ikw.jpg|left|200px]]
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[[Image:1ikw.png|left|200px]]
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{{STRUCTURE_1ikw| PDB=1ikw | SCENE= }}
{{STRUCTURE_1ikw| PDB=1ikw | SCENE= }}
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'''Wild Type HIV-1 Reverse Transcriptase in Complex with Efavirenz'''
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===Wild Type HIV-1 Reverse Transcriptase in Complex with Efavirenz===
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==Overview==
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The K103N substitution is a frequently observed HIV-1 RT mutation in patients who do not respond to combination-therapy. The drugs Efavirenz, MSC194 and PNU142721 belong to the recent generation of NNRTIs characterized by an improved resistance profile to the most common single point mutations within HIV-1 RT, including the K103N mutation. In the present study we present structural observations from Efavirenz in complex with wild-type protein and the K103N mutant and PNU142721 and MSC194 in complex with the K103N mutant. The structures unanimously indicate that the K103N substitution induces only minor positional adjustments of the three inhibitors and the residues lining the binding pocket. Thus, compared to the corresponding wild-type structures, these inhibitors bind to the mutant in a conservative mode rather than through major rearrangements. The structures implicate that the reduced inhibitory efficacy should be attributed to the changes in the chemical environment in the vicinity of the substituted N103 residue. This is supported by changes in hydrophobic and electrostatic interactions to the inhibitors between wild-type and K103N mutant complexes. These potent inhibitors accommodate to the K103N mutation by forming new interactions to the N103 side chain. Our results are consistent with the proposal by Hsiou et al. [Hsiou, Y., Ding, J., Das, K., Clark, A.D. Jr, Boyer, P.L., Lewi, P., Janssen, P.A., Kleim, J.P., Rosner, M., Hughes, S.H. &amp; Arnold, E. (2001) J. Mol. Biol. 309, 437-445] that inhibitors with good activity against the K103N mutant would be expected to have favorable interactions with the mutant asparagines side chain, thereby compensating for resistance caused by stabilization of the mutant enzyme due to a hydrogen-bond network involving the N103 and Y188 side chains.
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The line below this paragraph, {{ABSTRACT_PUBMED_11895437}}, adds the Publication Abstract to the page
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(as it appears on PubMed at http://www.pubmed.gov), where 11895437 is the PubMed ID number.
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{{ABSTRACT_PUBMED_11895437}}
==About this Structure==
==About this Structure==
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[[Category: Heterodimer]]
[[Category: Heterodimer]]
[[Category: Protein-inhibitor complex]]
[[Category: Protein-inhibitor complex]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 20:06:43 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 1 13:25:16 2008''

Revision as of 10:25, 1 July 2008

Image:1ikw.png

Template:STRUCTURE 1ikw

Wild Type HIV-1 Reverse Transcriptase in Complex with Efavirenz

Template:ABSTRACT PUBMED 11895437

About this Structure

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

Reference

Structural basis for the inhibitory efficacy of efavirenz (DMP-266), MSC194 and PNU142721 towards the HIV-1 RT K103N mutant., Lindberg J, Sigurdsson S, Lowgren S, Andersson HO, Sahlberg C, Noreen R, Fridborg K, Zhang H, Unge T, Eur J Biochem. 2002 Mar;269(6):1670-7. PMID:11895437

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