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chapter
7
Enzymes II: Regulation
Catalytic sites with low
affinity for substrate
Allosteric
site
Allosteric
site
TT state
Negative modulator preferentially
binds to the T form and maintains
the allosteric protein in the TT
conformation.
Positive modulator (or substrate
in positive homotropic
cooperativity) preferentially
binds to the R form and maintains
the allosteric protein in the
RR conformation.
Catalytic sites with high
FIG U R E 7-11
Schematic diagram of conformational changes of concerted model for a
dimeric allosteric enzyme. All subunits are either in the T-form with low
affinity for the substrate or in the R-form with high affinity for the substrate.
The concerted model has the following features. The al-
losteric protein exists only in two states: T or R. If, for ex-
ample, an allosteric protein contains two subunits, the sole
permissible conformation states are TT and RR (RT is not
allowed because R and T cannot form a stable pair). Thus,
in this model (also called the “all or none” model), symme-
try of the allosteric protein is preserved (Figure 7-11). It is
assumed that the T and R forms are in equilibrium, that sig-
nificant binding of ligand occurs
only
to the R form, and that
this binding shifts the equilibrium strongly in favor of for-
mation of the R form. Thus, a conformational change in one
subunit that occurs after it binds to a ligand causes a corre-
sponding change in all of the subunits without formation of
hybrid species. The concerted model accounts for the kinetic
behavior of many allosteric proteins, but it cannot account
for negative cooperativity; i.e., the decrease in affinity for a
ligand by the allosteric protein as the sites become occupied.
The sequential model proposes that as the ligand binds
to a subunit a conformational change is induced that stabi-
lizes the ligand-allosteric protein complex such that a sec-
ond ligand molecule is bound more readily than the first
(Figure 7-12). This effect is of positive cooperativity. How-
ever, if the initial binding of the ligand results in a ligand-
protein complex with decreased stability, the binding of addi-
tional ligand molecules, or ligand-induced substrate binding,
becomes increasingly difficult. This effect is negative coop-
erativity. In this model, the notion of symmetry is discarded,
since a conformational change induced by a ligand that binds
to a subunit also induces a conformational change in an ad-
jacent subunit. Figure 7-13 shows sequential transmission of
conformational changes through contiguous subunits upon
Catalytic sites with tow
affinity for substrate
Allosteric
site
TT state
Negative
modulator
Positive
modulator
Negative
cooperativity
©
TR state
Negative
modulator
Positive
modulator
Positive
cooperativity
RR state
FIG U R E 7-12
Schematic diagram of conformational changes of sequentially induced-fit
model for a dimeric allosteric enzyme. The TT conformation is
progressively converted to the RR conformation via the intermediate TR
conformation through cooperative interaction in the presence of the
positive modulator. In the presence of the negative modulator, the opposite
conformational changes occur. In this model, the notion of symmetry is
discarded and the concept of induced fit is emphasized.
ligand binding. The behavior of some allosteric proteins is
best explained by the concerted model, whereas for others the
sequential model is more appropriate. For many proteins, nei-
ther model is satisfactory and a more complex model may be
required.
T form
R form
FIG U R E 7-13
Sequential transmission of conformational changes through contiguous
subunits induced by a ligand (S). In idealized form, the conformational
changes proceed diagonally as the protein progressively binds ligand.
