PDBsum entry 3drs

Transferase

PDB id: 3drs

Contents

Protein chains

549 a.a. *

405 a.a. *

Ligands

R8D

* Residue conservation analysis

PDB id:

3drs

Name:

Transferase

Title:

HIV reverse transcriptase k103n mutant in complex with inhibitor r8d

Structure:

Reverse transcriptase/ribonuclease h. Chain: a. Fragment: gag-pol polyprotein p66 subunit. Synonym: rp66 rt. Engineered: yes. Mutation: yes. P66 rt. Chain: b. Fragment: gag-pol polyprotein p51 subunit.

Source:

Human immunodeficiency virus type 1. HIV-1. Organism_taxid: 11706. Strain: hxb2 isolate. Gene: gag-pol. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562

Resolution:

3.15Å R-factor: 0.187 R-free: 0.250

Authors:

Y.Yan,S.Prasad

Key ref:

T.J.Tucker et al. (2008). Discovery of 3-{5-[(6-amino-1H-pyrazolo[3,4-b]pyridine-3-yl)methoxy]-2-chlorophenoxy}-5-chlorobenzonitrile (MK-4965): a potent, orally bioavailable HIV-1 non-nucleoside reverse transcriptase inhibitor with improved potency against key mutant viruses. J Med Chem, 51, 6503-6511. PubMed id: 18826204

Date:

11-Jul-08 Release date: 14-Oct-08

Protein chain

P04585  (POL_HV1H2) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate HXB2)

Seq: 1435 a.a.

Struc: 549 a.a.*

Protein chain

P04585  (POL_HV1H2) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate HXB2)

Seq: 1435 a.a.

Struc: 405 a.a.*

* PDB and UniProt seqs differ at 3 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.3.4.23.16 - 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

J Med Chem 51:6503-6511 (2008)

PubMed id: 18826204

Discovery of 3-{5-[(6-amino-1H-pyrazolo[3,4-b]pyridine-3-yl)methoxy]-2-chlorophenoxy}-5-chlorobenzonitrile (MK-4965): a potent, orally bioavailable HIV-1 non-nucleoside reverse transcriptase inhibitor with improved potency against key mutant viruses.

T.J.Tucker, J.T.Sisko, R.M.Tynebor, T.M.Williams, P.J.Felock, J.A.Flynn, M.T.Lai, Y.Liang, G.McGaughey, M.Liu, M.Miller, G.Moyer, V.Munshi, R.Perlow-Poehnelt, S.Prasad, J.C.Reid, R.Sanchez, M.Torrent, J.P.Vacca, B.L.Wan, Y.Yan.

ABSTRACT

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been shown to be a key component of highly active antiretroviral therapy (HAART). The use of NNRTIs has become part of standard combination antiviral therapies producing clinical outcomes with efficacy comparable to other antiviral regimens. There is, however, a critical issue with the emergence of clinical resistance, and a need has arisen for novel NNRTIs with a broad spectrum of activity against key HIV-1 RT mutations. Using a combination of traditional medicinal chemistry/SAR analyses, crystallography, and molecular modeling, we have designed and synthesized a series of novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Further refinement of key compounds in this series to optimize physical properties and pharmacokinetics has resulted in the identification of 8e (MK-4965), which has high levels of potency against wild-type and key mutant viruses, excellent oral bioavailability and overall pharmacokinetics, and a clean ancillary profile.