1ikx: Difference between revisions

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[[Image:1ikx.jpg|left|200px]]
[[Image:1ikx.jpg|left|200px]]


{{Structure
<!--
|PDB= 1ikx |SIZE=350|CAPTION= <scene name='initialview01'>1ikx</scene>, resolution 2.80&Aring;
The line below this paragraph, containing "STRUCTURE_1ikx", 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=PNU:6-CHLORO-2-(1-FURO[2,3-C]PYRIDIN-5-YL-ETHYLSULFANYL)-PYRIMIDIN-4-YLAMINE'>PNU</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/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] </span>
or leave the SCENE parameter empty for the default display.
|GENE= BH10 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11676 Human immunodeficiency virus 1])
-->
|DOMAIN=
{{STRUCTURE_1ikx| PDB=1ikx  | SCENE= }}  
|RELATEDENTRY=
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1ikx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ikx OCA], [http://www.ebi.ac.uk/pdbsum/1ikx PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1ikx RCSB]</span>
}}


'''K103N Mutant HIV-1 Reverse Transcriptase in Complex with the Inhibitor PNU142721'''
'''K103N Mutant HIV-1 Reverse Transcriptase in Complex with the Inhibitor PNU142721'''
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[[Category: Lindberg, J.]]
[[Category: Lindberg, J.]]
[[Category: Unge, T.]]
[[Category: Unge, T.]]
[[Category: heterodimer]]
[[Category: Heterodimer]]
[[Category: protein-inhibitor complex]]
[[Category: Protein-inhibitor complex]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May  2 20:06:44 2008''
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 21:21:12 2008''

Revision as of 20:06, 2 May 2008

File:1ikx.jpg

Template:STRUCTURE 1ikx

K103N Mutant HIV-1 Reverse Transcriptase in Complex with the Inhibitor PNU142721


OverviewOverview

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. & 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.

About this StructureAbout this Structure

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

ReferenceReference

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 Page seeded by OCA on Fri May 2 20:06:44 2008

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