Cisbio eBook - 9

Trends in Protein-Protein Interactions Research | Protein-Protein Interactions: Lessons from the Past and Current Directions

researchers tried to predict function from the
direct interaction partner because it is believed
that proteins interacting with each other should
be involved in the same biological pathway
and may share similar functions. Zhang and his
colleagues went one step further and found that
the homologies of the interaction partners can
share similar function to the query protein. This
helps MetaGO to get broader functional insights
than that only from the direct interaction partners.

Low-resolution Protein
Structure Prediction
Another unique aspect of Zhang's pipeline is the
use of low-resolution protein structure prediction,
a traditional focus of Zhang's laboratory, to help
interpret protein functions. The interrogation of
both global and local structural alignments built
on the low-resolution predicted models makes
MetaGO detect far more functional homologies
than sequence-based homologous transferals. To
validate MetaGO, Zhang and colleagues tested
it on a large-scale set of 1,000 non-redundant

9 |

proteins and demonstrated its superiority over
peer approaches for functional prediction in the
community-wide blind experiments, such as
CAFA. "These results demonstrate the possibility
to deduce new functional insights that go far
beyond the traditional sequence homologybased predictions," says Zhang.

The study conducted in Vajda's group analyzed
a representative group of 93 proteins in which
the structure of the sites in unbound and ligandbound structures differs substantially. "According
to our paper, only a relatively limited number of
those sites are actually relevant or druggable,"
says Vajda.

"Studying cryptic sides got a boost when molecular dynamics became computationally feasible,
but when people identified large numbers of sites
on protein surfaces the question became how
useful those sites are," points out Sandor Vajda,
PhD, professor of biomedical engineering and
chemistry and director of the Biomolecular Engineering Research Center at Boston University. In a
recent study that explored the relative contributions of conformational selection and induced fit,
investigators in Vajda's group examined the structural origin of cryptic sites in proteins.

Some of the advances that helped design therapeutics to target protein-protein interfaces
include computation, molecular dynamics, and
the progression of X-ray crystallography. These
approaches made an increasing number of
structures available under different conditions,
including proteins co-crystalized with different
ligands. "And very frequently even small molecules that are not targeted, such as crystallization
oddities, can reveal the presence of a site," says
Vajda. These molecules that are occasionally
captured in X-ray crystal structures are frequently
called crystallization artifacts. "Often these crystallization artifacts can tell something about the
protein sites," adds Vajda.

"Our study on cryptic sites changes the way
druggability was seen longer ago," says Vajda.

Cisbio eBook

Table of Contents for the Digital Edition of Cisbio eBook

Cisbio eBook - 1
Cisbio eBook - 2
Cisbio eBook - 3
Cisbio eBook - Contents
Cisbio eBook - 5
Cisbio eBook - 6
Cisbio eBook - 7
Cisbio eBook - 8
Cisbio eBook - 9
Cisbio eBook - 10
Cisbio eBook - 11
Cisbio eBook - 12
Cisbio eBook - 13
Cisbio eBook - 14
Cisbio eBook - 15
Cisbio eBook - 16
Cisbio eBook - 17
Cisbio eBook - 18
Cisbio eBook - 19
Cisbio eBook - 20
Cisbio eBook - 21
Cisbio eBook - 22
Cisbio eBook - 23
Cisbio eBook - 24
Cisbio eBook - 25
Cisbio eBook - 26
Cisbio eBook - 27
Cisbio eBook - 28
Cisbio eBook - 29
Cisbio eBook - 30
Cisbio eBook - 31