1s1v
From Proteopedia
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| , resolution 2.60Å | |||||||
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| Ligands: | , | ||||||
| Gene: | POL (Human immunodeficiency virus type 1 (isolate HXB2)) | ||||||
| Activity: | RNA-directed DNA polymerase, with EC number 2.7.7.49 | ||||||
| Related: | 1VRT, 1RTH, 1VRU, 1RTI, 1RTJ, 1REV, 1RT1, 1RT2, 1KLM, 1RT3, 1RT4, 1RT5, 1RT6, 1RT7, 1C0T, 1C0U, 1C1B, 1C1C, 1DTQ, 1DTT, 1EP4, 1FK9, 1FKO, 1FKP, 1JLA, 1JLB, 1JLC, 1JLE, 1JLF, 1JLG, 1JKH, 1JLQ, 1LW0, 1LW2, 1LWC, 1LWE, 1LWF, 1S1T, 1S1U, 1S1W, 1S1X
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal structure of L100I mutant HIV-1 reverse transcriptase in complex with TNK-651
Overview
Leu100Ile, Val106Ala and Val108Ile are mutations in HIV-1 reverse transcriptase (RT) that are observed in the clinic and give rise to resistance to certain non-nucleoside inhibitors (NNRTIs) including the first-generation drug nevirapine. In order to investigate structural mechanisms of resistance for different NNRTI classes we have determined six crystal structures of mutant RT-inhibitor complexes. Val108 does not have direct contact with nevirapine in wild-type RT and in the RT(Val108Ile) complex the biggest change observed is at the distally positioned Tyr181 which is > 8 A from the mutation site. Thus in contrast to most NNRTI resistance mutations RT(Val108Ile) appears to act via an indirect mechanism which in this case is through alterations of the ring stacking interactions of the drug particularly with Tyr181. Shifts in side-chain and inhibitor positions compared to wild-type RT are observed in complexes of nevirapine and the second-generation NNRTI UC-781 with RT(Leu100Ile) and RT(Val106Ala), leading to perturbations in inhibitor contacts with Tyr181 and Tyr188. Such perturbations are likely to be a factor contributing to the greater loss of binding for nevirapine compared to UC-781 as, in the former case, a larger proportion of binding energy is derived from aromatic ring stacking of the inhibitor with the tyrosine side-chains. The differing resistance profiles of first and second generation NNRTIs for other drug resistance mutations in RT may also be in part due to this indirect mechanism.
About this Structure
1S1V is a Protein complex structure of sequences from Human immunodeficiency virus type 1 (isolate hxb2). Full crystallographic information is available from OCA.
Reference
Crystal structures of HIV-1 reverse transcriptases mutated at codons 100, 106 and 108 and mechanisms of resistance to non-nucleoside inhibitors., Ren J, Nichols CE, Chamberlain PP, Weaver KL, Short SA, Stammers DK, J Mol Biol. 2004 Feb 20;336(3):569-78. PMID:15095972
Page seeded by OCA on Sun Mar 30 23:36:14 2008
