The<unk>  protein contains three functional domains, the ATP-binding, protein-binding, and dimerizing domain, each of which playing a crucial role in the function of the protein. ATP binding The region of the protein near the N-terminus has a high-affinity ATP-binding site. The ATP binds to a sizable cleft in the side of protein, which is 15 Å (1.5 nanometres) deep. This cleft has a high affinity for ATP, and when given a suitable protein substrate,<unk>  cleaves the ATP into ADP and Pi. Direct inhibitors of ATP binding or allosteric inhibitors of either ATP binding or ATPase activity can block<unk>  function. Another interesting feature of the ATP-binding region of<unk>  is that it has a “lid” that is open during the ADP-bound state and closed in the ATP-bound state. In the open conformation, the lid has no intraprotein interaction, and when closed comes into contact with several residues. The contribution of this lid to the activity of<unk>  has been probed with site-directed mutagenesis. The Ala107Asp mutant stabilizing the closed conformation of the protein through the formation of additional hydrogen bonds substantially increases ATPase activity while leaving the AMP+PnP conformation unchanged. The ATPase-binding region of<unk>  is currently under intense study, because it is the principal binding site of drugs targeting this protein. Antitumor drugs targeting this section of<unk>  include the antibiotics geldanamycin, herbimycin, radicicol, deguelin, derrubone, macbecin, and beta-lactams. Protein binding The protein-binding region of<unk>  is located toward the C-terminus of the amino sequence. The<unk>  protein can adopt two major conformational states. The first is an open ATP-bound state and the second is a closed ADP-bound state. Thus, ATP hydrolysis drives what is commonly referred to as a “pincer-type” conformational change in the protein binding site.<unk> , while in the open conformation, leaves some hydrophobic residues exposed, to which unfolded and misfolded proteins that have unusual hydrophobic regions exposed are recruited with high affinity. When a bound substrate is in place, the energy-releasing ATP hydrolysis by the ATPase function near the N-terminal domain forces conformational changes that clamp the<unk>  down onto the substrate. In a reaction similar to that of other molecular clamp proteins like GyrB and MutL, this site drives virtually all of the protein folding functions that<unk>  plays a role in. In contrast, MutL and GyrB function as topoisomerases and use a charge clamp with a high amount of positively charged sidechains that is electrostatically attracted to the negative backbone of DNA. The ability of<unk>  to clamp onto proteins allows it to perform several functions including assisting folding, preventing aggregation, and facilitating transport.
Hsp90
HspE7
Bcl-xL
Bcl-2
Caspase-9
Mad2
IKK2
NLRP3