Ras: Ras GAP Complex
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info on Ras: RasGAP complex.
For more information see
Biochemistry Online: Chapter 9C-7 - Small G proteins, GAPs and GEFs
II. General Structure
The superfamily of small G proteins have a common 20K molecular weight
catalytic domain with 5 alpha helices, 6 beta strands and connecting loops.
The G1 loop binds phosphate groups as is often called the P-loop (as in the
case of protein tyrosine phosphatases). Its binds GTP and GDP and has
GTPase activity. The small G proteins are "active" in the GTP bound
form. Hydrolysis of GTP to GDP causes the protein to become inactive in
cartoon: Ras (yellow)
Important parts of Ras necessary for GTP binding:
- phosphate-binding (P loop), residues 10 to 16;
- switch regions I (30 to 37) and II (60 to 76), which are flexible loops
which sandwich GTP;
P loop (red); Switch I (orange); Switch II (blue)
Same as above but with Arg 789 on GAP, rendered as ball and stick. This Arg will stabilize the transition state on GTP hydrolysis
Hydrolysis of the gamma phosphate of GTP by water would proceed by a pentavalent transition state with two axial and three equatorial ligands to the P.
Developing charge in the transition state would usually be stablilized by catalytic residues in the catalytic domain of Ras. However, Ras is a poor GTPase. The
Arg 789 on the GAP is positioned in the Ras:GAP complex to provide the extra stabilization.
The Arg 789 is almost in the same position as Arg 178 in the Galpha inhibitor
subunit of a heterotrimeric G protein which inhibits GPCR signaling.
Same as above but with GDP and AFl3 (to mimic the pentavalent transition state analog for GTP cleavage)
Same as above but add Gln 61 (purple) on Ras which is essential for catalysis;
There is no general base nearby to abstract a proton and make water a better nucleophile for catalysis. Gln 61 might play such a role.