Medicinal Chemistry

mapped by Gilman and his group. This chain of reactions is shown in figure 2.4.
Membrane receptors that operate through adenylate cyclase can do so either by activat-
ing the amplifier (see below) or by inhibiting it. When the receptor is occupied by its
ligand, it forms a transient complex with a guanyl nucleotide binding protein, which is
occupied by GDP. These protein transducers—either stimulatory (Gs) or inhibitory
(Gi)—become activated in the binding process. In the ternary ligand–receptor–GGDP
complex, the GDP is exchanged for a GTP, which triggers the release of the αssubunit
of the αβγtrimer Gsprotein. The βandγsubunits are also released. The active αs
subunit then combines with the adenylate cyclase (AC) enzyme (the amplifier),
which produces cAMP, the second messenger. The active Gsstate is terminated by a
ligand-activated GTPase, which hydrolyzes the bound GTP to GDP. Presumably, the
G protein is then reconstituted from the three subunits in the inactive form, ready for
the next binding cycle with an occupied receptor. It must be kept in mind that the recep-
tors, the G proteins, and the cyclase interact in a mobile system by collision coupling,
and thus a large diversity of receptors can activate the same population of G proteins
and cyclase.
The final step in signal transduction is the action of cAMP on the regulatory subunit
of the enzyme, protein kinase A. This ubiquitous enzyme then phosphorylates and acti-
vates enzymes with functions specific to different cells and organs. In fat cells, protein
kinase A activates lipase, which mobilizes fatty acids; in muscle and liver cells, it reg-
ulates glycogenolysis and glycogen synthesis.
The molecular properties of G proteins and their subunits, as well as the structural basis
of the interactions among the α,β, and γsubunits of G proteins and between these sub-
units and the associated receptor, has been immensely facilitated by X-ray crystallographic

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5

Inside

Outside

GDP

GTP GDP

GTP

GTP

GDP

ATP cAMP

AC AC

RT RR RR RT

Pi

as

as

as

b b

a

g a b

Gs

LL

L

g

g

L

Figure 2.4 Model of adenylate cyclase activation. (1) The receptor, in the tense (off) conformation
(RT), binds ligand (L) to form (2) the activated ligand–receptor complex (RR–L), which can now
undergo collision coupling with the stimulatory guanyl-nucleotide binding protein trimer (GS).
(3) The ternary complex (L–RR–GS) is activated by an exchange of the GDP bound on the G pro-
tein for a GTP. (4) The ternary complex dissociates into inactive receptor (RT), the ligand (L), the
βγsubunits of the G protein, and (5) the activated αSsubunit of the G protein. (6) The active αS
subunit binds to adenylate cyclase (AC) and activates it, initiating cAMP synthesis from ATP.
(7) The αSsubunit is inactivated by hydrolysis of GTP to GDP and inorganic phosphate (Pi); the
αSsubunit–GDP complex recycles by reassociating with the βγsubunits.