1S1X

Crystal structure of V108I mutant HIV-1 reverse transcriptase in complex with nevirapine

Summary for 1S1X

• Entry DOI: 10.2210/pdb1s1x/pdb
• Related: 1C0T 1C0U 1C1B 1C1C 1DTQ 1DTT 1EP4 1FK9 1FKO 1FKP 1JKH 1JLA 1JLB 1JLC 1JLE 1JLF 1JLG 1JLQ 1KLM 1LW0 1LW2 1LWC 1LWE 1LWF 1REV 1RT1 1RT2 1RT3 1RT4 1RT5 1RT6 1RT7 1RTH 1RTI 1RTJ 1S1T 1S1U 1S1V 1S1W 1VRT 1VRU
• Descriptor: Reverse transcriptase, 11-CYCLOPROPYL-5,11-DIHYDRO-4-METHYL-6H-DIPYRIDO[3,2-B:2',3'-E][1,4]DIAZEPIN-6-ONE, ... (4 entities in total)
• Functional Keywords: hiv-1 reverse transcriptase, aids, nnrti, nevirapine, drug resistance mutations, transferase
• Biological source: Human immunodeficiency virus 1; More
• Cellular location: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P04585 P04585
• Total number of polymer chains: 2
• Total formula weight: 116288.34

Authors

Ren, J.,Nichols, C.E.,Chamberlain, P.P.,Stammers, D.K. (deposition date: 2004-01-07, release date: 2004-06-29, Last modification date: 2021-11-10)

Primary citation

Ren, J.,Nichols, C.E.,Chamberlain, P.P.,Weaver, K.L.,Short, S.A.,Stammers, D.K.
Crystal structures of HIV-1 reverse transcriptases mutated at codons 100, 106 and 108 and mechanisms of resistance to non-nucleoside inhibitors
J.Mol.Biol., 336:569-578, 2004

PubMed Abstract: 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.

PubMed: 15095972
DOI: 10.1016/j.jmb.2003.12.055

Experimental method

X-RAY DIFFRACTION (2.8 Å)