BioPHYSICAL chemistry

determine the structures of the proteome; that is, all the proteins
that are found in an organism (Stauton et al. 2003). In addition,
with its application in the determination of protein structures,
NMR is also used widely as a tool for drug discovery. Many of the
technicaldevelopments have proven useful for such efforts, in par-
ticular the screening of low-molecular-mass molecules with novel
ligands to the desired target molecule (Villar et al. 2004).

Determination of macromolecular structures

The chemical shifts of most protons in proteins lie in the range of
1– 9 ppm. The chemical shifts for all 20 amino acid residues have
been measured (Table 16.2). These values provide guidelines as to
the expected values for the different amino acid residues: in par-
ticular, how the protons are coupled within an amino acid residue.
Determination of the structure requires that all of the peaks must
be assigned individually to specific protons in the protein. To make
this assignment the primary structure of the protein must be known
as each of the 20 amino acids, with their different side chains, has a
characteristic NMR pattern. NMR experiments are used to determine the
structure of a protein by providing constraints on the distances between
backbone protons, neighboring side chains, and spatially close side chains.
Programs use this information together with the known geometric con-
straints, using energy minimization to generate possible structures.

Research direction: spinal muscular atrophy

Spinal muscular atrophy is a genetic, motor neuron disease caused by
progressive degeneration of motor neurons in the spinal cord. The dis-
order causes weakness and wasting of the voluntary muscles. Weakness
is often more severe in the legs than in the arms. Childhood spinal mus-
cular atrophies are all autosomal recessive diseases. This means that they
run in families and more than one case is likely to occur in siblings or
cousins of the same generation. Parents usually have no symptoms, but
carry the gene. The gene for spinal muscular atrophy has been identified
and accurate diagnostic tests exist.
The SMN1gene encodes a protein consisting of 294 amino acid residues
(Lefebvre et al. 1995; Lorson et al. 1998; Holzbaur 2004). The SMN pro-
tein has several sequence motifs: a highly basic region in residues 28 –91,
two proline-rich regions in residues 195–248, and a tyrosine/glycine-rich
region in residues 261–278. The protein sequence does not share homo-
logy with any other proteins, except for residues 92–144, which were
identified as being homologous to a Tudor domain. How the protein func-
tions to ensure the survival of motor neurons remains uncertain. It is

CHAPTER 16 MAGNETIC RESONANCE 357

54.74

Magnetic field

Figure 16.12Magic-angle

spinning with the spinning

at 54.74° relative to the

applied magnetic field.