Solution structure of anti-HIV-1 and anti-tumor protein MAP30: structural insights into its multiple functions.
We present the solution structure of MAP30, a plant protein with anti-HIV and anti-tumor activities. Structural analysis and subsequent biochemical assays lead to several novel discoveries. First, MAP30 acts like a DNA glycosylase/apurinic (ap) lyase, an additional activity distinct from its known RNA N-glycosidase activity toward the 28S rRNA. Glycosylase/ap lyase activity explains MAP30's apparent inhibition of the HIV-1 integrase, MAP30's ability to irreversibly relax supercoiled DNA, and may be an alternative cytotoxic pathway that contributes to MAP30's anti-HIV/anti-tumor activities. Second, two distinct, but contiguous, subsites are responsible for MAP30's glycosylase/ap lyase activity. Third, Mn2+ and Zn2+ interact with negatively charged surfaces next to the catalytic sites, facilitating DNA substrate binding instead of directly participating in catalysis.
Wang
Y X
YX
Molecular Structural Biology Laboratory, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892-4310, USA.
Neamati
N
N
Jacob
J
J
Palmer
I
I
Stahl
S J
SJ
Kaufman
J D
JD
Huang
P L
PL
Huang
P L
PL
Winslow
H E
HE
Pommier
Y
Y
Wingfield
P T
PT
Lee-Huang
S
S
Bax
A
A
Torchia
D A
DA
D019380:Anti-HIV Agents / Q000737:chemistry* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D019757:Carbon-Oxygen Lyases / Q000378:metabolism; D002413:Cations, Divalent; D045647:DNA Glycosylases; D004279:DNA, Viral / Q000378:metabolism; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D043223:Deoxyribonuclease IV (Phage T4-Induced); D016325:HIV Long Terminal Repeat; D015497:HIV-1; D006801:Humans; D008670:Metals; D008958:Models, Molecular; D009699:N-Glycosyl Hydrolases / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D010940:Plant Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011687:Purines / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D054790:Ribosome Inactivating Proteins, Type 2; D012996:Solutions
D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D002413:Cations, Divalent; D004279:DNA, Viral; C066347:MAP30 protein, Momordica charantia; D008670:Metals; D010940:Plant Proteins; D011687:Purines; D011993:Recombinant Fusion Proteins; D054790:Ribosome Inactivating Proteins, Type 2; D012996:Solutions; D043223:Deoxyribonuclease IV (Phage T4-Induced); D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; D019757:Carbon-Oxygen Lyases; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase