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ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis
Paul Towler1, Bart Staker, Sridhar G Prasad
1Drug Discovery and Protein Sciences, Millennium Pharmaceuticals, Incorporated, Cambridge, Massachusetts 02139, USA.
The Journal of Biological Chemistry
|February 3, 2004
Summary
Angiotensin-converting enzyme 2 (ACE2) structures reveal inhibitor-induced movements crucial for catalysis. These findings provide insights into ACE2
Area of Science:
- Biochemistry
- Structural Biology
- Enzymology
Background:
- Angiotensin-converting enzyme 2 (ACE2) is a type I integral membrane protein involved in heart function and serves as a receptor for SARS-CoV.
- Understanding ACE2's structure and function is critical due to its physiological roles and viral interactions.
Purpose of the Study:
- To elucidate the structural basis of ACE2 activity and inhibitor binding.
- To gain insights into the catalytic mechanisms and substrate specificity of ACE2.
Main Methods:
- X-ray crystallography was employed to determine the structures of native and inhibitor-bound ACE2 extracellular domains.
- Structures were solved to 2.2- and 3.0-Å resolution.
- Comparative structural analysis was performed to identify conformational changes upon inhibitor binding.
Main Results:
- The crystal structures revealed an inhibitor-dependent hinge-bending movement (approx. 16°) in the catalytic subdomain.
- The potent inhibitor MLN-4760 binds to the active site, highlighting key interactions.
- Active site residue differences between ACE2 and ACE explain the shift from peptidyl dipeptidase to carboxypeptidase activity.
Conclusions:
- Structural data reveals dynamic conformational changes in ACE2 upon inhibitor binding, essential for catalysis.
- MLN-4760 binding interactions offer a detailed view of ACE2 active site residues and substrate specificity.
- Specific ACE2 active site substitutions account for its distinct enzymatic activity compared to ACE.