PDBsum entry 1k6c

Hydrolase

PDB id: 1k6c

Contents

Protein chains

99 a.a. *

Ligands

ACT ×5

MK1

Waters ×119

* Residue conservation analysis

PDB id:

1k6c

Name:

Hydrolase

Title:

Lack of synergy for inhibitors targeting a multi-drug resistant HIV-1 protease

Structure:

Pol polyprotein. Chain: a, b. Fragment: HIV-1 protease, residues 57-155. Engineered: yes. Mutation: yes

Source:

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

Biol. unit:

Dimer (from PQS)

Resolution:

2.20Å R-factor: 0.194 R-free: 0.231

Authors:

C.A.Schiffer

Key ref:

N.M.King et al. (2002). Lack of synergy for inhibitors targeting a multi-drug-resistant HIV-1 protease. Protein Sci, 11, 418-429. PubMed id: 11790852 DOI: 10.1110/ps.25502

Date:

15-Oct-01 Release date: 06-Feb-02

Protein chains

P35963  (POL_HV1Y2) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate YU-2)

Seq: 1435 a.a.

Struc: 99 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: E.C.2.7.7.- - ?????
• Enzyme class 2: 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: 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: E.C.3.1.-.-
• Enzyme class 5: 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: E.C.3.1.26.13 - retroviral ribonuclease H.
• Enzyme class 7: 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: 10.1110/ps.25502

Protein Sci 11:418-429 (2002)

PubMed id: 11790852

Lack of synergy for inhibitors targeting a multi-drug-resistant HIV-1 protease.

N.M.King, L.Melnick, M.Prabu-Jeyabalan, E.A.Nalivaika, S.S.Yang, Y.Gao, X.Nie, C.Zepp, D.L.Heefner, C.A.Schiffer.

ABSTRACT

The three-dimensional structures of indinavir and three newly synthesized indinavir analogs in complex with a multi-drug-resistant variant (L63P, V82T, I84V) of HIV-1 protease were determined to approximately 2.2 A resolution. Two of the three analogs have only a single modification of indinavir, and their binding affinities to the variant HIV-1 protease are enhanced over that of indinavir. However, when both modifications were combined into a single compound, the binding affinity to the protease variant was reduced. On close examination, the structural rearrangements in the protease that occur in the tightest binding inhibitor complex are mutually exclusive with the structural rearrangements seen in the second tightest inhibitor complex. This occurs as adaptations in the S1 pocket of one monomer propagate through the dimer and affect the conformation of the S1 loop near P81 of the other monomer. Therefore, structural rearrangements that occur within the protease when it binds to an inhibitor with a single modification must be accounted for in the design of inhibitors with multiple modifications. This consideration is necessary to develop inhibitors that bind sufficiently tightly to drug-resistant variants of HIV-1 protease to potentially become the next generation of therapeutic agents.

Selected figure(s)

Figure 1.
Fig. 1. (a) A chemical schematic diagram of indinavir, with the protease substrate subsites labeled. (b) A schematic representation of the synthesis pathway for indinavir analogs.

Figure 2.
Fig. 2. Ribbon diagrams of two views of the drug-resistant variant of HIV-1 protease dimer (in cyan and yellow) bound to indinavir (in ma- genta). The three modifications L63P, V82T, I84V are displayed and la- beled in blue and green for each monomer, respectively. Figures were made with MIDAS (Ferrin et al. 1988).

The above figures are reprinted from an Open Access publication published by the Protein Society: Protein Sci (2002, 11, 418-429) copyright 2002.

Figures were selected by an automated process.