Chemistry Reference
In-Depth Information
Figure 4.2
The
N
- linked glycan (Man
9
GlcNAc
2
) on HIV- 1 gp120.
conjugates exhibit a broad variety of additional biological functions such as pre-
sentation of target structures for microorganisms, toxins and antibodies, control
of protein half-life, modulation of protein function or provision of ligands for
specifi c binding events. Multivalent interactions are now understood to be a ubiq-
uitous strategy that has evolved in nature for a wide range of functions, that pro-
vides numerous and unique benefi ts that are not achievable with monovalent
interactions. This observation is also present at the molecular level with multiple
carbohydrate-protein interactions that are responsible for several biological events
(for further details on mechanism of carbohydrate-protein interactions, please see
Chapter 13). Indeed, saccharides are expressed on the majority of mammalian cell
surfaces and are bound to proteins (' glycoproteins ' ) or lipids ( ' glycolipids ' ) that are
entangled in the cell membranes and clustered in multiantennary confi gurations
[2] (for further details, please see also Chapters 6 and 10). Surprisingly, although
these multiple protein-carbohydrate interactions are responsible for several crucial
biological events, it has been shown that, on a per-saccharide basis, these interac-
tions are characterized by rather weak association constant (milli- to micromolar)
with limited specifi city and selectivity (for further details, please see Chapter 14).
However, these interactions are transformed into very potent attractive forces,
dramatically and naturally reinforced, when multiple ligand copies are presented
to similarly clustered receptors. This phenomena, resulting in a synergic and
cooperative effect, is known as the 'glycoside cluster or dendritic effect' and was
initially observed with asialoglycoprotein receptors found on hepatocytes (please
see survey fi gure in Chapter 19 showing the oligomer, and Chapter 15 for the
history on Ashwell's discovery of the C-type lectin) [3]. In its widespread version,
it is usually assumed that this effect has its source in the enhanced affi nity of a
given multivalent glycoside toward a carbohydrate recognition domain (CRD) by
fully occupying one active site at a time (for further details, please see Chapter 16
providing X-ray illustrations on CRDs of various Ca
2+
- dependent lectins). The
phenomenon is now widely accepted as having its basis on stabilization by mac-
roscopic ' cross - linking glycocluster effects '. With all these observed advantages in
