 |
PDBsum entry 1b87
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
DOI no:
|
Structure
7:497-507
(1999)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Crystal structure of an aminoglycoside 6'-N-acetyltransferase: defining the GCN5-related N-acetyltransferase superfamily fold.
|
|
L.E.Wybenga-Groot,
K.Draker,
G.D.Wright,
A.M.Berghuis.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
BACKGROUND: The predominant mechanism of antibiotic resistance employed by
pathogenic bacteria against the clinically used aminoglycosides is chemical
modification of the drug. The detoxification reactions are catalyzed by enzymes
that promote either the phosphorylation, adenylation or acetylation of
aminoglycosides. Structural studies of these aminoglycoside-modifying enzymes
may assist in the development of therapeutic agents that could circumvent
antibiotic resistance. In addition, such studies may shed light on the
development of antibiotic resistance and the evolution of different enzyme
classes. RESULTS: The crystal structure of the aminoglycoside-modifying enzyme
aminoglycoside 6'-N-acetyltransferase type li (AAC(6')-li) in complex with the
cofactor acetyl coenzyme A has been determined at 2.7 A resolution. The
structure establishes that this acetyltransferase belongs to the GCN5-related
N-acetyltransferase superfamily, which includes such enzymes as the histone
acetyltransferases GCN5 and Hat1. CONCLUSIONS: Comparison of the AAC(6')-li
structure with the crystal structures of two other members of this superfamily,
Serratia marcescens aminoglycoside 3-N-acetyltransferase and yeast histone
acetyltransferase Hat1, reveals that of the 84 residues that are structurally
similar, only three are conserved and none can be implicated as catalytic
residues. Despite the negligible sequence identity, functional studies show that
AAC(6')-li possesses protein acetylation activity. Thus, AAC(6')-li is both a
structural and functional homolog of the GCN5-related histone acetyltransferases.
|
|
|
|
|
|
| |
Selected figure(s)
|
|
|
|
| |
|
|
|
|
| |
The above figure is
reprinted
by permission from Cell Press:
Structure
(1999,
7,
497-507)
copyright 1999.
|
|
| |
Figure was
selected
by an automated process.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Literature references that cite this PDB file's key reference
|
|
|
| |
PubMed id
|
|
Reference
|
|
|
|
|
|
L.A.Freiburger,
O.M.Baettig,
T.Sprules,
A.M.Berghuis,
K.Auclair,
and
A.K.Mittermaier
(2011).
Competing allosteric mechanisms modulate substrate binding in a dimeric enzyme.
|
| |
Nat Struct Mol Biol,
18,
288-294.
|
|
|
|
|
|
|
X.Yan,
T.O.Akinnusi,
A.T.Larsen,
and
K.Auclair
(2011).
Synthesis of 4'-aminopantetheine and derivatives to probe aminoglycoside N-6'-acetyltransferase.
|
| |
Org Biomol Chem,
9,
1538-1546.
|
|
|
|
|
|
|
G.De Pascale,
and
G.D.Wright
(2010).
Antibiotic resistance by enzyme inactivation: from mechanisms to solutions.
|
| |
Chembiochem,
11,
1325-1334.
|
|
|
|
|
|
|
J.L.Houghton,
K.D.Green,
W.Chen,
and
S.Garneau-Tsodikova
(2010).
The future of aminoglycosides: the end or renaissance?
|
| |
Chembiochem,
11,
880-902.
|
|
|
|
|
|
|
M.Morar,
and
G.D.Wright
(2010).
The genomic enzymology of antibiotic resistance.
|
| |
Annu Rev Genet,
44,
25-51.
|
|
|
|
|
|
|
M.S.Ramirez,
and
M.E.Tolmasky
(2010).
Aminoglycoside modifying enzymes.
|
| |
Drug Resist Updat,
13,
151-171.
|
|
|
|
|
|
|
F.Gao,
X.Yan,
and
K.Auclair
(2009).
Synthesis of a phosphonate-linked aminoglycoside-coenzyme a bisubstrate and use in mechanistic studies of an enzyme involved in aminoglycoside resistance.
|
| |
Chemistry,
15,
2064-2070.
|
|
|
|
|
|
|
M.Demendi,
and
C.Creuzenet
(2009).
Cj1123c (PglD), a multifaceted acetyltransferase from Campylobacter jejuni.
|
| |
Biochem Cell Biol,
87,
469-483.
|
|
|
|
|
|
|
M.Morar,
K.Bhullar,
D.W.Hughes,
M.Junop,
and
G.D.Wright
(2009).
Structure and mechanism of the lincosamide antibiotic adenylyltransferase LinB.
|
| |
Structure,
17,
1649-1659.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
A.M.Davies,
R.Tata,
F.X.Chauviac,
B.J.Sutton,
and
P.R.Brown
(2008).
Structure of a putative acetyltransferase (PA1377) from Pseudomonas aeruginosa.
|
| |
Acta Crystallogr Sect F Struct Biol Cryst Commun,
64,
338-342.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
F.Gao,
X.Yan,
O.Zahr,
A.Larsen,
K.Vong,
and
K.Auclair
(2008).
Synthesis and use of sulfonamide-, sulfoxide-, or sulfone-containing aminoglycoside-CoA bisubstrates as mechanistic probes for aminoglycoside N-6'-acetyltransferase.
|
| |
Bioorg Med Chem Lett,
18,
5518-5522.
|
|
|
|
|
|
|
F.Maurice,
I.Broutin,
I.Podglajen,
P.Benas,
E.Collatz,
and
F.Dardel
(2008).
Enzyme structural plasticity and the emergence of broad-spectrum antibiotic resistance.
|
| |
EMBO Rep,
9,
344-349.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
S.Shakil,
R.Khan,
R.Zarrilli,
and
A.U.Khan
(2008).
Aminoglycosides versus bacteria--a description of the action, resistance mechanism, and nosocomial battleground.
|
| |
J Biomed Sci,
15,
5.
|
|
|
|
|
|
|
T.Lombès,
G.Bégis,
F.Maurice,
S.Turcaud,
T.Lecourt,
F.Dardel,
and
L.Micouin
(2008).
NMR-guided fragment-based approach for the design of AAC(6')-Ib ligands.
|
| |
Chembiochem,
9,
1368-1371.
|
|
|
|
|
|
|
D.Iino,
Y.Takakura,
M.Kuroiwa,
R.Kawakami,
Y.Sasaki,
T.Hoshino,
K.Ohsawa,
A.Nakamura,
and
S.Yajima
(2007).
Crystallization and preliminary crystallographic analysis of hygromycin B phosphotransferase from Escherichia coli.
|
| |
Acta Crystallogr Sect F Struct Biol Cryst Commun,
63,
685-688.
|
|
|
|
|
|
|
D.L.Siehl,
L.A.Castle,
R.Gorton,
and
R.J.Keenan
(2007).
The molecular basis of glyphosate resistance by an optimized microbial acetyltransferase.
|
| |
J Biol Chem,
282,
11446-11455.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
F.Hou,
C.W.Chu,
X.Kong,
K.Yokomori,
and
H.Zou
(2007).
The acetyltransferase activity of San stabilizes the mitotic cohesin at the centromeres in a shugoshin-independent manner.
|
| |
J Cell Biol,
177,
587-597.
|
|
|
|
|
|
|
G.D.Wright
(2007).
The antibiotic resistome: the nexus of chemical and genetic diversity.
|
| |
Nat Rev Microbiol,
5,
175-186.
|
|
|
|
|
|
|
N.M.Llewellyn,
Y.Li,
and
J.B.Spencer
(2007).
Biosynthesis of butirosin: transfer and deprotection of the unique amino acid side chain.
|
| |
Chem Biol,
14,
379-386.
|
|
|
|
|
|
|
M.N.Hung,
E.Rangarajan,
C.Munger,
G.Nadeau,
T.Sulea,
and
A.Matte
(2006).
Crystal structure of TDP-fucosamine acetyltransferase (WecD) from Escherichia coli, an enzyme required for enterobacterial common antigen synthesis.
|
| |
J Bacteriol,
188,
5606-5617.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
S.Jana,
and
J.K.Deb
(2006).
Molecular understanding of aminoglycoside action and resistance.
|
| |
Appl Microbiol Biotechnol,
70,
140-150.
|
|
|
|
|
|
|
A.M.Davies,
R.Tata,
R.Agha,
B.J.Sutton,
and
P.R.Brown
(2005).
Crystal structure of a putative phosphinothricin acetyltransferase (PA4866) from Pseudomonas aeruginosa PAC1.
|
| |
Proteins,
61,
677-679.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
A.Pourreza,
M.Witherspoon,
J.Fox,
J.Newmark,
D.Bui,
and
M.E.Tolmasky
(2005).
Mutagenesis analysis of a conserved region involved in acetyl coenzyme A binding in the aminoglycoside 6'-N-acetyltransferase type Ib encoded by plasmid pJHCMW1.
|
| |
Antimicrob Agents Chemother,
49,
2979-2982.
|
|
|
|
|
|
|
C.T.Lemke,
J.Hwang,
B.Xiong,
N.P.Cianciotto,
and
A.M.Berghuis
(2005).
Crystallization and preliminary crystallographic analysis of an aminoglycoside kinase from Legionella pneumophila.
|
| |
Acta Crystallogr Sect F Struct Biol Cryst Commun,
61,
606-608.
|
|
|
|
|
|
|
D.L.Burk,
B.Xiong,
C.Breitbach,
and
A.M.Berghuis
(2005).
Structures of aminoglycoside acetyltransferase AAC(6')-Ii in a novel crystal form: structural and normal-mode analyses.
|
| |
Acta Crystallogr D Biol Crystallogr,
61,
1273-1279.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
F.Forouhar,
I.S.Lee,
J.Vujcic,
S.Vujcic,
J.Shen,
S.M.Vorobiev,
R.Xiao,
T.B.Acton,
G.T.Montelione,
C.W.Porter,
and
L.Tong
(2005).
Structural and functional evidence for Bacillus subtilis PaiA as a novel N1-spermidine/spermine acetyltransferase.
|
| |
J Biol Chem,
280,
40328-40336.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
F.Gao,
X.Yan,
O.M.Baettig,
A.M.Berghuis,
and
K.Auclair
(2005).
Regio- and chemoselective 6'-N-derivatization of aminoglycosides: bisubstrate inhibitors as probes to study aminoglycoside 6'-N-acetyltransferases.
|
| |
Angew Chem Int Ed Engl,
44,
6859-6862.
|
|
|
|
|
|
|
M.Podar,
J.R.Eads,
and
T.H.Richardson
(2005).
Evolution of a microbial nitrilase gene family: a comparative and environmental genomics study.
|
| |
BMC Evol Biol,
5,
42.
|
|
|
|
|
|
|
M.W.Vetting,
L.P.de Carvalho,
S.L.Roderick,
and
J.S.Blanchard
(2005).
A novel dimeric structure of the RimL Nalpha-acetyltransferase from Salmonella typhimurium.
|
| |
J Biol Chem,
280,
22108-22114.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
C.S.Riesenfeld,
R.M.Goodman,
and
J.Handelsman
(2004).
Uncultured soil bacteria are a reservoir of new antibiotic resistance genes.
|
| |
Environ Microbiol,
6,
981-989.
|
|
|
|
|
|
|
M.W.Vetting,
S.Magnet,
E.Nieves,
S.L.Roderick,
and
J.S.Blanchard
(2004).
A bacterial acetyltransferase capable of regioselective N-acetylation of antibiotics and histones.
|
| |
Chem Biol,
11,
565-573.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
D.D.Boehr,
K.A.Draker,
K.Koteva,
M.Bains,
R.E.Hancock,
and
G.D.Wright
(2003).
Broad-spectrum peptide inhibitors of aminoglycoside antibiotic resistance enzymes.
|
| |
Chem Biol,
10,
189-196.
|
|
|
|
|
|
|
D.D.Boehr,
S.I.Jenkins,
and
G.D.Wright
(2003).
The molecular basis of the expansive substrate specificity of the antibiotic resistance enzyme aminoglycoside acetyltransferase-6'-aminoglycoside phosphotransferase-2". The role of ASP-99 as an active site base important for acetyl transfer.
|
| |
J Biol Chem,
278,
12873-12880.
|
|
|
|
|
|
|
J.S.Blanchard
(2003).
Resisting bacterial drug resistance.
|
| |
Chem Biol,
10,
104-106.
|
|
|
|
|
|
|
P.Pfister,
S.Hobbie,
Q.Vicens,
E.C.Böttger,
and
E.Westhof
(2003).
The molecular basis for A-site mutations conferring aminoglycoside resistance: relationship between ribosomal susceptibility and X-ray crystal structures.
|
| |
Chembiochem,
4,
1078-1088.
|
|
|
|
|
|
|
D.H.Fong,
and
A.M.Berghuis
(2002).
Substrate promiscuity of an aminoglycoside antibiotic resistance enzyme via target mimicry.
|
| |
EMBO J,
21,
2323-2331.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
S.S.Hegde,
T.K.Dam,
C.F.Brewer,
and
J.S.Blanchard
(2002).
Thermodynamics of aminoglycoside and acyl-coenzyme A binding to the Salmonella enterica AAC(6')-Iy aminoglycoside N-acetyltransferase.
|
| |
Biochemistry,
41,
7519-7527.
|
|
|
|
|
|
|
A.Shmara,
N.Weinsetel,
K.J.Dery,
R.Chavideh,
and
M.E.Tolmasky
(2001).
Systematic analysis of a conserved region of the aminoglycoside 6'-N-acetyltransferase type Ib.
|
| |
Antimicrob Agents Chemother,
45,
3287-3292.
|
|
|
|
|
|
|
D.D.Boehr,
W.S.Lane,
and
G.D.Wright
(2001).
Active site labeling of the gentamicin resistance enzyme AAC(6')-APH(2") by the lipid kinase inhibitor wortmannin.
|
| |
Chem Biol,
8,
791-800.
|
|
|
|
|
|
|
E.Azucena,
and
S.Mobashery
(2001).
Aminoglycoside-modifying enzymes: mechanisms of catalytic processes and inhibition.
|
| |
Drug Resist Updat,
4,
106-117.
|
|
|
|
|
|
|
S.Magnet,
T.Lambert,
P.Courvalin,
and
J.S.Blanchard
(2001).
Kinetic and mutagenic characterization of the chromosomally encoded Salmonella enterica AAC(6')-Iy aminoglycoside N-acetyltransferase.
|
| |
Biochemistry,
40,
3700-3709.
|
|
|
|
|
|
|
F.Dyda,
D.C.Klein,
and
A.B.Hickman
(2000).
GCN5-related N-acetyltransferases: a structural overview.
|
| |
Annu Rev Biophys Biomol Struct,
29,
81.
|
|
|
|
|
|
|
L.P.Kotra,
J.Haddad,
and
S.Mobashery
(2000).
Aminoglycosides: perspectives on mechanisms of action and resistance and strategies to counter resistance.
|
| |
Antimicrob Agents Chemother,
44,
3249-3256.
|
|
|
|
|
|
|
Y.Yan,
N.A.Barlev,
R.H.Haley,
S.L.Berger,
and
R.Marmorstein
(2000).
Crystal structure of yeast Esa1 suggests a unified mechanism for catalysis and substrate binding by histone acetyltransferases.
|
| |
Mol Cell,
6,
1195-1205.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
E.M.Khalil,
J.De Angelis,
M.Ishii,
and
P.A.Cole
(1999).
Mechanism-based inhibition of the melatonin rhythm enzyme: pharmacologic exploitation of active site functional plasticity.
|
| |
Proc Natl Acad Sci U S A,
96,
12418-12423.
|
|
|
|
|
|
|
G.D.Wright
(1999).
Aminoglycoside-modifying enzymes.
|
| |
Curr Opin Microbiol,
2,
499-503.
|
|
|
|
|
|
|
R.Chavideh,
S.Sholly,
D.Panaite,
and
M.E.Tolmasky
(1999).
Effects of F171 mutations in the 6'-N-acetyltransferase type Ib [AAC(6')-Ib] enzyme on susceptibility to aminoglycosides.
|
| |
Antimicrob Agents Chemother,
43,
2811-2812.
|
|
|
|
|
|
The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
|
|
Links
