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1fk9
From Proteopedia
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| , resolution 2.5Å | |||||||
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| Ligands: | , | ||||||
| Activity: | RNA-directed DNA polymerase, with EC number 2.7.7.49 | ||||||
| Related: | 1rtv, 1rth, 1vru, 1rti, 1rtj, 1rev, 1rt1, 1rt2, 1klm, 1rt3, 1rt4, 1rt5, 1rt6, 1rt7, 1c0t, 1c0u, 1c1b, 1c1c, 1dtq, 1dtt, 1ep4
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
CRYSTAL STRUCTURE OF HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH DMP-266(EFAVIRENZ)
Overview
BACKGROUND: Efavirenz is a second-generation non-nucleoside inhibitor of HIV-1 reverse transcriptase (RT) that has recently been approved for use against HIV-1 infection. Compared with first-generation drugs such as nevirapine, efavirenz shows greater resilience to drug resistance mutations within HIV-1 RT. In order to understand the basis for this resilience at the molecular level and to help the design of further-improved anti-AIDS drugs, we have determined crystal structures of efavirenz and nevirapine with wild-type RT and the clinically important K103N mutant. RESULTS: The relatively compact efavirenz molecule binds, as expected, within the non-nucleoside inhibitor binding pocket of RT. There are significant rearrangements of the drug binding site within the mutant RT compared with the wild-type enzyme. These changes, which lead to the repositioning of the inhibitor, are not seen in the interaction with the first-generation drug nevirapine. CONCLUSIONS: The repositioning of efavirenz within the drug binding pocket of the mutant RT, together with conformational rearrangements in the protein, could represent a general mechanism whereby certain second-generation non-nucleoside inhibitors are able to reduce the effect of drug-resistance mutations on binding potency.
About this Structure
1FK9 is a Protein complex structure of sequences from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.
Reference
Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase., Ren J, Milton J, Weaver KL, Short SA, Stuart DI, Stammers DK, Structure. 2000 Oct 15;8(10):1089-94. PMID:11080630
Page seeded by OCA on Sun Mar 30 20:24:34 2008
