PDBsum entry 4ztf

Transferase/DNA/inhibitor

PDB id: 4ztf

Contents

Protein chains

368 a.a.

184 a.a.

DNA/RNA

Ligands

GOL ×4

X2P

SO4 ×3

Metals

_MG ×3

_ZN

Waters ×159

PDB id:

4ztf

Name:

Transferase/DNA/inhibitor

Title:

Crystal structure of the prototype foamy virus intasome with a 2- pyridinone aminal inhibitor

Structure:

Integrase. Chain: a, b. Synonym: pr125pol. Engineered: yes. 19 nucleotide preprocessed pfv donor DNA (non-transferred strand). Chain: c. Engineered: yes. 17 nucleotide preprocessed pfv donor DNA (transferred

Source:

Human spumaretrovirus. Sfvcpz(hu). Organism_taxid: 11963. Gene: pol. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Organism_taxid: 11963

Resolution:

2.70Å R-factor: 0.192 R-free: 0.215

Authors:

D.J.Klein,S.Patel

Key ref:

I.T.Raheem et al. (2015). Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors. J Med Chem, 58, 8154-8165. PubMed id: 26397965 DOI: 10.1021/acs.jmedchem.5b01037

Date:

14-May-15 Release date: 07-Oct-15

Protein chain

P14350  (POL_FOAMV) -  Pro-Pol polyprotein from Human spumaretrovirus

Seq: 1143 a.a.

Struc: 368 a.a.*

Protein chain

P14350  (POL_FOAMV) -  Pro-Pol polyprotein from Human spumaretrovirus

Seq: 1143 a.a.

Struc: 184 a.a.*

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

DNA/RNA chains

A-T-T-G-T-C-A-T-G-G-A-A-T-T-T-C-G-C-A 19 bases

T-G-C-G-A-A-A-T-T-C-C-A-T-G-A-C-A 17 bases

Enzyme reactions

• Enzyme class 2: Chains A, B: E.C.2.7.7.- - ?????
• Enzyme class 3: 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 4: 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 5: Chains A, B: E.C.3.1.-.-
• Enzyme class 6: Chains A, B: E.C.3.1.26.4 - ribonuclease H.
• Reaction: Endonucleolytic cleavage to 5'-phosphomonoester.
• Enzyme class 7: Chains A, B: E.C.3.4.23.- - ?????

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: 10.1021/acs.jmedchem.5b01037

J Med Chem 58:8154-8165 (2015)

PubMed id: 26397965

Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors.

I.T.Raheem, A.M.Walji, D.Klein, J.M.Sanders, D.A.Powell, P.Abeywickrema, G.Barbe, A.Bennet, K.Childers, M.Christensen, S.D.Clas, D.Dubost, M.Embrey, J.Grobler, M.J.Hafey, T.J.Hartingh, D.J.Hazuda, J.T.Kuethe, J.McCabe Dunn, M.D.Miller, K.P.Moore, A.Nolting, N.Pajkovic, S.Patel, Z.Peng, V.Rada, P.Rearden, J.D.Schreier, J.Sisko, T.G.Steele, J.F.Truchon, J.Wai, M.Xu, P.J.Coleman.

ABSTRACT

The search for new molecular constructs that resemble the critical two-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here we present the discovery of a new class of HIV integrase strand transfer inhibitors based on the 2-pyridinone core of MK-0536. These efforts led to the identification of two lead compounds with excellent antiviral activity and preclinical pharmacokinetic profiles to support a once-daily human dose prediction. Dose escalating PK studies in dog revealed significant issues with limited oral absorption and required an innovative prodrug strategy to enhance the high-dose plasma exposures of the parent molecules.