PDBsum entry 1ikv

Transferase

PDB id: 1ikv

Contents

Protein chains

556 a.a. *

404 a.a. *

Ligands

EFZ

* Residue conservation analysis

PDB id:

1ikv

Name:

Transferase

Title:

K103n mutant HIV-1 reverse transcriptase in complex with efivarenz

Structure:

Pol polyprotein. Chain: a. Synonym: reverse transcriptase. Engineered: yes. Mutation: yes. Pol polyprotein. Chain: b. Synonym: reverse transcriptase. Engineered: yes.

Source:

Human immunodeficiency virus 1. Organism_taxid: 11676. Gene: bh10. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Tetramer (from PQS)

Resolution:

3.00Å R-factor: 0.228 R-free: 0.294

Authors:

J.Lindberg,T.Unge

Key ref:

J.Lindberg et al. (2002). Structural basis for the inhibitory efficacy of efavirenz (DMP-266), MSC194 and PNU142721 towards the HIV-1 RT K103N mutant. Eur J Biochem, 269, 1670-1677. PubMed id: 11895437 DOI: 10.1046/j.1432-1327.2002.02811.x

Date:

07-May-01 Release date: 06-Jun-01

Protein chain

P03366  (POL_HV1B1) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate BH10)

Seq: 1447 a.a.

Struc: 556 a.a.*

Protein chain

P03366  (POL_HV1B1) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate BH10)

Seq: 1447 a.a.

Struc: 404 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class 1: Chains A, B: E.C.2.7.7.- - ?????
• Enzyme class 2: Chains A, B: E.C.2.7.7.49 - RNA-directed Dna polymerase.
• Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
• Enzyme class 3: Chains A, B: E.C.2.7.7.7 - DNA-directed Dna polymerase.
• Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
• Enzyme class 4: Chains A, B: E.C.3.1.-.-
• Enzyme class 5: Chains A, B: E.C.3.1.13.2 - exoribonuclease H.
• Reaction: Exonucleolytic cleavage to 5'-phosphomonoester oligonucleotides in both 5'- to 3'- and 3'- to 5'-directions.
• Enzyme class 6: Chains A, B: E.C.3.1.26.13 - retroviral ribonuclease H.
• Enzyme class 7: Chains A, B: E.C.3.4.23.16 - HIV-1 retropepsin.
• Reaction: Specific for a P1 residue that is hydrophobic, and P1' variable, but often Pro.

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1046/j.1432-1327.2002.02811.x

Eur J Biochem 269:1670-1677 (2002)

PubMed id: 11895437

Structural basis for the inhibitory efficacy of efavirenz (DMP-266), MSC194 and PNU142721 towards the HIV-1 RT K103N mutant.

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

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.

Selected figure(s)

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.

Figures were selected by an automated process.