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Fig. 3. The ATPase activity of Hsp90 is abrogated by the
slou45 mutation. (A) Hsp90a domain structure
(amino acid numbers of domain boundaries are shown beneath; known functions of
regions are indicated by black bars). The positions and consequences of
mutations in three slo alleles, u45, tu44c and tm201, are also
illustrated beneath. The equivalent residue locations of yeast Hsp90 as
represented in B are shown above. (B) Pymol diagram showing critical
binding interactions of ADP with yeast Hsp90. Dotted blue lines are hydrogen
bonds; amino acid residues (corresponding residue numbers in zebrafish are in
parentheses and are also indicated in A) involved are in green; water
molecules are cyan balls; residues packed against the C-
atom of Gly83
are shown in cyan. Illustrated residues are conserved between yeast and
zebrafish, except Ser138/Thr149 and Ser140/His151 (grey), which are
conservative substitutions unlikely to cause major structural changes. Binding
of ATP/ADP to the Hsp90 N-terminal domain involves highly conserved
interactions including the carboxylate side-chain of Asp79 and main-chain
carboxyl of Leu34, via a tightly bound water molecule, to the exocyclic N6 of
adenine. The same Asp79 also interacts via another tightly bound water to the
N1 imino-nitrogen of the adenine. This same water is bound by an interaction
with the side-chain hydroxyl of Thr171 and main-chain amide of Gly83. An
aspartic acid residue substitution at Gly83 (mimicking the u45 mutation) would
lead to steric clashes likely to disrupt critical hydrogen bonding
interactions with ADP/ATP. (C) ATPase activity of yeast Hsp90, human
HSP90 and their u45-mimic mutants. ATPase activity of the yeast G83D
and human G91D mutants is negligible relative to corresponding wild type.
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