2ic3
From Proteopedia
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|PDB= 2ic3 |SIZE=350|CAPTION= <scene name='initialview01'>2ic3</scene>, resolution 3.000Å | |PDB= 2ic3 |SIZE=350|CAPTION= <scene name='initialview01'>2ic3</scene>, resolution 3.000Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= | + | |LIGAND= <scene name='pdbligand=HBY:(S)-4-ISOPROPOXYCARBONYL-6-METHOXY-3-METHYLTHIOMETHYL-3,4-DIHYDROQUINOXALIN-2(1H)-THIONE'>HBY</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene> |
| - | |ACTIVITY= [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] | + | |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> |
|GENE= pol ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11676 Human immunodeficiency virus 1]) | |GENE= pol ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11676 Human immunodeficiency virus 1]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[2iaj|2IAJ]], [[1bqm|1BQM]], [[1dlo|1DLO]], [[1uwb|1UWB]], [[1sv5|1SV5]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ic3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ic3 OCA], [http://www.ebi.ac.uk/pdbsum/2ic3 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2ic3 RCSB]</span> | ||
}} | }} | ||
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[[Category: Arnold, E.]] | [[Category: Arnold, E.]] | ||
[[Category: Das, K.]] | [[Category: Das, K.]] | ||
| - | [[Category: HBY]] | ||
| - | [[Category: MN]] | ||
[[Category: aid]] | [[Category: aid]] | ||
[[Category: drug design]] | [[Category: drug design]] | ||
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[[Category: rt]] | [[Category: rt]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:42:17 2008'' |
Revision as of 00:42, 31 March 2008
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| , resolution 3.000Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , | ||||||
| Gene: | pol (Human immunodeficiency virus 1) | ||||||
| Activity: | RNA-directed DNA polymerase, with EC number 2.7.7.49 | ||||||
| Related: | 2IAJ, 1BQM, 1DLO, 1UWB, 1SV5
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
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.
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
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