PDBsum entry 1ikx

Transferase

PDB id: 1ikx

Contents

Protein chains

557 a.a. *

427 a.a. *

Ligands

PNU

Waters ×61

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Structural basis for the inhibitory efficacy of efavirenz (dmp-266), Msc194 and pnu142721 towards the HIV-1 rt k103n mutant.

Authors

J.Lindberg, S.Sigurdsson, S.Löwgren, H.O.Andersson, C.Sahlberg, R.Noréen, K.Fridborg, H.Zhang, T.Unge.

Ref.

Eur J Biochem, 2002, 269, 1670-1677. [DOI no: 10.1046/j.1432-1327.2002.02811.x]

PubMed id

11895437

Abstract

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.

Figure 1.
Fig. 1. Structures of NNRTIs. Chemical structure of the NNRTIs (A) Efavirenz, (B) PNU142721, and (C) MSC194. Atom numbering was included for clarification of Table 3 Go-.

Figure 3.
Fig. 3. Superimposition of Efavirenz bound to wild-type and K103N mutant RT NNIBPs. Stereoview of the superimposition of Efavirenz bound to the NNIBP of wild-type RT and the K103N mutant. Residue side chains characteristic of the NNIBP are included from each inhibitor complex and colored green for wild-type and maroon for the K103N mutant. The superimposition was carried out using all atoms from the residues within 4.0 Å from the inhibitors (V189, K101, K103N, V179, Y181, Y188, F227, W229, L234, H235, Y318 and E138).

The above figures are reprinted by permission from the Federation of European Biochemical Societies: Eur J Biochem (2002, 269, 1670-1677) copyright 2002.