Triose phosphate isomerase, which gave its name to the TIM barrel domain, catalyzes the isomerizaation of dihydroxyacetone phosphate to glyceraldehyde 3-phosphate.

• The protein is active as a dimer of identical units

• The catalytic residues are Lys13, His95, and Glu165 (picked out below in violet)

  Unliganded Triose Phosphate Isomerase (8tim)	With an Inhibitor Bound (1tph)

• The enzyme closes around a substrate or inhibitor, as illustrated above, by folding a flap composed of residues 166-176 (blue)

• As with adenylate kinase, multiple conformations involving the flap can be found in other structures in the pdb:

  Another Open Conformer of TIM (1ypi)

• It is argued from this observation that both these enzymes exist in a mixture of conformers when unliganded

A backbone alignment (rmsd = 1.27 A) indicates the extent of change upon binding:

Alignment of 8tim and 1tph
(Flap open in red, closed in green)

Doruker and coworkers [ Biochem., 2006, 45, 1173] use a coarse-grained model to examine the pathway between the open and closed conformations of the flap.

• Their data suggest that Thr172, at the tip of the flap, moves about 7 Å

  Closeup of Flap and Inhibitor

• The catalytic Glu165 moves about 2 Å and the side chain of Trp rotates about 50 degrees

Here is a movie showing the flap motion in one chain:

Flap Closure in TIM

Clearly the old Fischer idea of the enzyme and substrate as rigidly defined lock and key is dead.

Profound conformational changes when enzyme and substrate interact are the rule, not the exception.