PDBsum entry 5frm

Recombination

PDB id: 5frm

Contents

Protein chains

367 a.a.

183 a.a.

DNA/RNA

Ligands

SO4 ×5

MES

GOL ×8

WA5

Metals

_ZN

_MG ×2

Waters ×135

PDB id:

5frm

Name:

Recombination

Title:

Crystal structure of the prototype foamy virus (pfv) intasome in complex with magnesium and the insti xz384 (compound 4a)

Structure:

Pfv integrase. Chain: a, b. Synonym: pro-pol polyprotein pr125pol, p87pro-rt-rnaseh, p65pro-rt, p42in, pfv integrase. Engineered: yes. 5'-d( Ap Tp Tp Gp Tp Cp Ap Tp Gp Gp Ap Ap Tp Tp Tp Cp Gp Cp A)-3'. Chain: c. Engineered: yes.

Source:

Human spumaretrovirus. Organism_taxid: 11963. Strain: hsrv2. Variant: pol. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_variant: pc2. Synthetic: yes. Synthetic construct.

Resolution:

2.58Å R-factor: 0.186 R-free: 0.203

Authors:

D.P.Maskell,V.E.Pye,P.Cherepanov

Key ref:

X.Z.Zhao et al. (2016). HIV-1 Integrase Strand Transfer Inhibitors with Reduced Susceptibility to Drug Resistant Mutant Integrases. Acs Chem Biol, 11, 1074-1081. PubMed id: 26808478 DOI: 10.1021/acschembio.5b00948

Date:

18-Dec-15 Release date: 17-Feb-16

Protein chain

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

Seq: 1143 a.a.

Struc: 367 a.a.*

Protein chain

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

Seq: 1143 a.a.

Struc: 183 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/acschembio.5b00948

Acs Chem Biol 11:1074-1081 (2016)

PubMed id: 26808478

HIV-1 Integrase Strand Transfer Inhibitors with Reduced Susceptibility to Drug Resistant Mutant Integrases.

X.Z.Zhao, S.J.Smith, D.P.Maskell, M.Metifiot, V.E.Pye, K.Fesen, C.Marchand, Y.Pommier, P.Cherepanov, S.H.Hughes, T.R.Burke.

ABSTRACT

HIV integrase (IN) strand transfer inhibitors (INSTIs) are among the newest anti-AIDS drugs; however, mutant forms of IN can confer resistance. We developed noncytotoxic naphthyridine-containing INSTIs that retain low nanomolar IC50 values against HIV-1 variants harboring all of the major INSTI-resistant mutations. We found by analyzing crystal structures of inhibitors bound to the IN from the prototype foamy virus (PFV) that the most successful inhibitors show striking mimicry of the bound viral DNA prior to 3'-processing and the bound host DNA prior to strand transfer. Using this concept of "bi-substrate mimicry," we developed a new broadly effective inhibitor that not only mimics aspects of both the bound target and viral DNA but also more completely fills the space they would normally occupy. Maximizing shape complementarity and recapitulating structural components encompassing both of the IN DNA substrates could serve as a guiding principle for the development of new INSTIs.