PDBsum entry 4be0

Transferase/DNA

PDB id: 4be0

Contents

Protein chains

368 a.a.

184 a.a.

DNA/RNA

Ligands

SO4 ×3

GOL ×5

BF3

Metals

_ZN

_MG ×2

Waters ×227

PDB id:

4be0

Name:

Transferase/DNA

Title:

Pfv intasome with inhibitor xz-115

Structure:

Pfv integrase. Chain: a, b. Synonym: integrase, in, p42in. Engineered: yes. 19 nucleotide preprocessed pfv donor DNA (non-transferred strand). Chain: c. Synonym: 5' utr. Engineered: yes.

Source:

Human spumaretrovirus. Organism_taxid: 11963. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Organism_taxid: 11963

Resolution:

2.68Å R-factor: 0.185 R-free: 0.218

Authors:

S.Hare,P.Cherepanov

Key ref:

M.Métifiot et al. (2013). Activities, crystal structures, and molecular dynamics of dihydro-1H-isoindole derivatives, inhibitors of HIV-1 integrase. Acs Chem Biol, 8, 209-217. PubMed id: 23075516 DOI: 10.1021/cb300471n

Date:

08-Oct-12 Release date: 31-Oct-12

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/cb300471n

Acs Chem Biol 8:209-217 (2013)

PubMed id: 23075516

Activities, crystal structures, and molecular dynamics of dihydro-1H-isoindole derivatives, inhibitors of HIV-1 integrase.

M.Métifiot, K.Maddali, B.C.Johnson, S.Hare, S.J.Smith, X.Z.Zhao, C.Marchand, T.R.Burke, S.H.Hughes, P.Cherepanov, Y.Pommier.

ABSTRACT

On the basis of a series of lactam and phthalimide derivatives that inhibit HIV-1 integrase, we developed a new molecule, XZ-259, with biochemical and antiviral activities comparable to raltegravir. We determined the crystal structures of XZ-259 and four other derivatives in complex with the prototype foamy virus intasome. The compounds bind at the integrase-Mg(2+)-DNA interface of the integrase active site. In biochemical and antiviral assays, XZ-259 inhibits raltegravir-resistant HIV-1 integrases harboring the Y143R mutation. Molecular modeling is also presented suggesting that XZ-259 can bind in the HIV-1 intasome with its dimethyl sulfonamide group adopting two opposite orientations. Molecular dynamics analyses of the HIV-1 intasome highlight the importance of the viral DNA in drug potency.