|
Figure 3.
Architecture of the engineered loop preceding the αC-helix
in the CDK4 (cyan)/cyclin D1 (orange) structure. (A) Akin to
CDK2 and CDK6 (see Fig. S4) the apex of the loop is stabilized
by hydrogen bonds from the loop main chain to a highly-conserved
lysine (Lys[D1]112) and glutamate (Glu[D1]141) on the cyclin.
The second glutamate (Glu[K4]44′) from the GE′E′G
insertion mimics the interactions formed by the glutamate in the
CDK6 structure. The loop is further stabilized by intramolecular
H-bonds, which are not observed in either the CDK2 or CDK6
structures. A cyclin D1 Lys[D1]112–Glu mutation results in
aberrant CDK4/cyclin D1 complex assembly and activation. (B)
Residues in the vicinity of cyclin D1 (orange) Lys[D1]114. The
Lys[D1]114–Glu mutation results in defective CDK4/cyclin D1
complex formation. Lys[D1]114 sits within an acidic environment
formed by Glu[D1]74, Glu[D1]75, Glu[D1]76, Asp[D1]159, and
Glu[D1]162. It would be anticipated that introduction of an
additional negative charge into this environment would be highly
destabilizing and significantly perturb correct CDK/cyclin
association.
|
