Chemistry Reference
In-Depth Information
Molecular. dynamics. simulations. of. both. the. mono-Zn. and. di-Zn. B1. MβLs. in.
complex. with. different. types. of. β-lactams. (e.g.,. benzylpenicillin,. imipenem,. and.
cefotaxime).pointed.to.a.few.crucial.interactions.for.binding.recognition.across.sub-
class.B1.(Scheme.1.1,.Figure.1.6),.regardless.of.the.metal.content.(i.e.,.in.both.mono-
Zn.BcII,.and.di-Zn.CcrA). 192-195 .(1).A.water.bridges.the.β-lactam.carboxylate.group.
and. the. metal. center. (WAT. in. ES. in. Scheme. 1.2. and. Figures. 1.6. and. 1.7).. WAT.
H-bonds.to.the.β-lactam.carboxylate.moiety.it.is.highly.persistent.within.the.cata-
lytic.pocket.and.is.spatially.conserved.in.mono.and.dizinc.systems.and.functional.to.
binding.recognition.pattern.found.for.different.β-lactams.in.the.pocket.(Figure.1.6)..
When.two.Zn.metals.are.bound.at.the.active.site.(like.in.CcrA),.WAT.is.bound.to.the.
second.Zn.(Zn2),.completing.its.coordination.shell..(2).A.water-mediated.salt.bridge.
is.maintained.between.the.β-lactam.carboxylate.moiety.and.Lys224.(a.residue.which.
is.conserved.in.most.B1.enzymes).(Scheme.1.2.and.Figure.1.6).
di-Zn CcrA from bacteroides fragilis
Cefotaxime
EP
ES
O
TS
N
O
S
O
S
S
Asn233
N
O
3
NH 2
NH
N
5
(wat)
N
H
4
N
S
O
(wat)
8
Asn233
COO -
O -
Lys224
(wat)
COO -
O
H
HO
O -
O
HO
WAT'
WAT'
Asn233
His196
WAT
H
H
WAT
His196
O
H
His196
H
O
WAT -
18(2) kcal mol -1
H
O
His263
His263
O
OH -
Zn2
Zn1
His263
Zn2
Zn1
His118
O
His118
H
Zn2
Zn1
Cys221
His118
Cys221
His116
H
O
O
His116
Cys221
O
O
His116
O
O
Asp120
Asp120
Asp120
Cefotaxime binding
Products release
3H mono-Zn bcll from bacillus cereus
O
ES
Cefotaxime
TS1
INT
N
S
O
S
N
S
O
N
NH 2
3
(wat)
O
NH
O -
Asn233
5
S
O
N
(wat)
Asn233
4
N
8
O -
(wat)
Lys224
O -
O
OH -
Asn233
Lys224
O
O
O -
Lys224
WAT
H
O
His196
O
His196
O -
(wat)
H
H
O
H
WAT
H
Cys221
Zn1
Cys221
O
His196
H
Zn1
His118
O
H
His118
N
OH -
19(2) kcal mol -1
12(2) kcal mol -1
WAT
H
O
N
H
O
O
His116
His116
Zn1
His118
O
His263
O
Cys221
H
Asp120
His116
O
Asp120
O
Arg121
Asp120
WAT'
S
21(2) kcal mol -1
Cefotaxime binding
S
(wat)
Asn233
NH
(wat)
Asn233
N
Lys224
O
Products release
O
Lys224
O
O
O -
HO
H
O -
His196
His196
O
OH +
H
WAT'
H
H
WAT'
O
O
H
O
His118
Zn1
His118
O
Zn1
H
H
Cys221
Cys221
His116
His116
OH
O
O
O
EP
TS2
Asp120
Asp120
SCHEME 1.2  Di-Zn.and.mono-Zn.reaction.mechanisms.in.B1.MβLs.as.found.in.QM/MM.
studies.(see.also.Figures.1.6.and.1.7)..(Adapted.from.Dal.Peraro,.M.,.Vila,.A.J.,.Carloni,.P.,.
and.Klein,.M.L.,. J. Am. Chem. Soc. ,.129,.2808,.2007.)
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