PDBsum entry 1mu2

Transferase

PDB id: 1mu2

Contents

Protein chains

538 a.a. *

402 a.a. *

Ligands

SO4 ×22

GOL ×5

Waters ×286

* Residue conservation analysis

PDB id:

1mu2

Name:

Transferase

Title:

Crystal structure of HIV-2 reverse transcriptase

Structure:

HIV-2 rt. Chain: a. Synonym: reverse transcriptase. Engineered: yes. Mutation: yes. HIV-2 rt. Chain: b. Fragment: residues 6-431. Synonym: reverse transcriptase.

Source:

Human immunodeficiency virus 2. Organism_taxid: 11709. Strain: prod. Gene: pol. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Dimer (from PQS)

Resolution:

2.35Å R-factor: 0.192 R-free: 0.240

Authors:

J.Ren,L.E.Bird,P.P.Chamberlain,G.B.Stewart-Jones,D.I.Stuart, D.K.Stammers

Key ref:

J.Ren et al. (2002). Structure of HIV-2 reverse transcriptase at 2.35-A resolution and the mechanism of resistance to non-nucleoside inhibitors. Proc Natl Acad Sci U S A, 99, 14410-14415. PubMed id: 12386343 DOI: 10.1073/pnas.222366699

Date:

23-Sep-02 Release date: 30-Oct-02

Protein chain

P04584  (POL_HV2RO) -  Gag-Pol polyprotein from Human immunodeficiency virus type 2 subtype A (isolate ROD)

Seq: 1464 a.a.

Struc: 538 a.a.*

Protein chain

P04584  (POL_HV2RO) -  Gag-Pol polyprotein from Human immunodeficiency virus type 2 subtype A (isolate ROD)

Seq: 1464 a.a.

Struc: 402 a.a.*

* PDB and UniProt seqs differ at 5 residue positions (black crosses)

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.3.4.23.47 - HIV-2 retropepsin.

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: 10.1073/pnas.222366699

Proc Natl Acad Sci U S A 99:14410-14415 (2002)

PubMed id: 12386343

Structure of HIV-2 reverse transcriptase at 2.35-A resolution and the mechanism of resistance to non-nucleoside inhibitors.

J.Ren, L.E.Bird, P.P.Chamberlain, G.B.Stewart-Jones, D.I.Stuart, D.K.Stammers.

ABSTRACT

The HIV-2 serotype of HIV is a cause of disease in parts of the West African population, and there is evidence for its spread to Europe and Asia. HIV-2 reverse transcriptase (RT) demonstrates an intrinsic resistance to non-nucleoside RT inhibitors (NNRTIs), one of two classes of anti-AIDS drugs that target the viral RT. We report the crystal structure of HIV-2 RT to 2.35 A resolution, which reveals molecular details of the resistance to NNRTIs. HIV-2 RT has a similar overall fold to HIV-1 RT but has structural differences within the "NNRTI pocket" at both conserved and nonconserved residues. The structure points to the role of sequence differences that can give rise to unfavorable inhibitor contacts or destabilization of part of the binding pocket at positions 101, 106, 138, 181, 188, and 190. We also present evidence that the conformation of Ile-181 compared with the HIV-1 Tyr-181 could be a significant contributory factor to this inherent drug resistance of HIV-2 to NNRTIs. The availability of a refined structure of HIV-2 RT will provide a stimulus for the structure-based design of novel non-nucleoside inhibitors that could be used against HIV-2 infection.

Selected figure(s)

Figure 2.
Fig 2. (A) Stereo diagram comparing the NNRTI site of an unliganded HIV-1 RT and the corresponding region of HIV-2 RT. The HIV-1 RT is colored in gray, and the main chain and side chains of HIV-2 RT are shown in green and orange, respectively. (B) Stereo diagram showing part of the HIV-2 RT p55 subunit containing the Ile-181 and Leu-188 side chains (blue and green) overlapped with the corresponding region of the p66 subunit in the nevirapine-bound HIV-1 RT (orange and red). Nevirapine is drawn as ball-and-sticks and colored by atoms. (C) Stereo diagram showing a cavity located at the junction of the p68 palm, p68 connection, and p55 fingers domains (ribbon and coils colored in green, red, and blue, respectively). Side chains of the residues lining the cavity, a bound glycerol and a sulfate are shown in ball-and-stick representation, and are colored by atoms, with carbon atoms in cyan for the side chains and black for the glycerol. Water molecules in the cavity are shown as small red spheres. Larger red spheres label the C position of the three catalytic Asp residues at the polymerase active site. Nevirapine colored in gray is shown to mark the NNRTI site in HIV-1 RT. The dashed yellow sticks indicate the four H-bonds from the glycerol to the carbonyl oxygen of Gly-99, the main-chain nitrogen of Ala-101, and a water molecule.

Figure 3.
Fig 3. Comparison of the structure around residues 181 and 188 of the p55 subunit in HIV-2 RT with that of p51 subunit in HIV-1 RT. The main chains are shown as ribbons and coils, and side chains as ball-and-stick representations, with HIV-1 RT colored orange and red, and HIV-2 RT blue and green.

Figures were selected by an automated process.