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to calculate the probabilities of observing the “open” and “closed” conformations of
this protein in the absence of ribose (RBP is involved in the ribose transport across
the plasma membrane in
E. coli.
). They found that RBP can exist in
closed
and
open
conformations in 4% and 96% of the time, respectively, in the absence of ribose
(Fig.
7.1
).
Most interestingly they find that ribose can bind only to the closed form, thereby
shifting the equilibrium toward the closed conformation. Therefore, their findings
can be represented schematically as follows:
RBP
open
$
RBP
closed
(7.11)
Ribose
þ
RBP
closed
$
Ribose
RBP
closed
(7.12)
Processes
7.11
and
7.12
can be accounted for by PFH which is based on the
generalized Franck-Condon principle or the Principle of Slow and Fast Processes
(PSFP) (see Sect.
2.2.3
), in terms of the differential kinetic properties between RBP
(i.e.,
slow
conformation change) and ribose molecules (i.e.,
fast
diffusion in and out
of the binding pocket of RBP) secondary to their size difference, which dictates
that, in order for ribose to bind to RBP, the slower conformational changes of RBP
must precede the faster thermal motions (i.e., collisions) of ribose against the
binding site of RBP.
Many hormones and cytokines exert their biological actions on cells by binding
to their target receptors which undergo dimerization. Biologists have been assum-
ing that hormone/cytokine binding “induces” dimerization of receptor monomers,
R, most likely because of the influence of the
induced fit hypothesis
(Koshland
1958; Berg et al. 2002):
R
þ
H
$
R
H
þ
R
$
R
H
R
!
Biological Actions
(7.13)
In contrast, PFH suggests the following alternative mechanism:
R
þ
R
þ
H
$
R
R
þ
H
$
R
H
R
!
Biological Actions
(7.14)
In other words, PFH predicts that receptors can (and indeed must) dimerize
before hormones can bind, again for the same kinetic reason as indicated above:
The thermal motions of R's are so slow relative to that of H that, unless R's are
already brought close enough to each other via Brownian motions, H could not be
“captured” before it bounces back out from R into the surrounding medium.
The X-ray crystallographic investigations on erythropoietin receptor (EpoR)
provide another evidence for PFH. EpoR is the receptor for EPO, a glycoprotein
(i.e., a protein covalently linked to sugar residues) that, upon binding to EpoR,
regulates the proliferation, differentiation, and maturation of red blood cells. EPOR
was thought to be activated by EPO-induced dimerization, but the X-ray structural
