7Q3Y

Structure of full-length, monomeric, soluble somatic angiotensin I-converting enzyme showing the N- and C-terminal ellipsoid domains

Summary for 7Q3Y

• Entry DOI: 10.2210/pdb7q3y/pdb
• Related: 7Q4C 7Q4D 7Q4E
• EMDB information: 13797 13799 13801 13802 13803 13804
• Descriptor: Angiotensin-converting enzyme, alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• Functional Keywords: zinc metalloprotease dicarboxypeptidase glycoprotein, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 146511.13

Authors

Lubbe, L.,Sewell, B.T.,Sturrock, E.D. (deposition date: 2021-10-29, release date: 2022-07-20, Last modification date: 2022-08-24)

Primary citation

Lubbe, L.,Sewell, B.T.,Woodward, J.D.,Sturrock, E.D.
Cryo-EM reveals mechanisms of angiotensin I-converting enzyme allostery and dimerization.
Embo J., 41:e110550-e110550, 2022

PubMed Abstract: Hypertension (high blood pressure) is a major risk factor for cardiovascular disease, which is the leading cause of death worldwide. The somatic isoform of angiotensin I-converting enzyme (sACE) plays a critical role in blood pressure regulation, and ACE inhibitors are thus widely used to treat hypertension and cardiovascular disease. Our current understanding of sACE structure, dynamics, function, and inhibition has been limited because truncated, minimally glycosylated forms of sACE are typically used for X-ray crystallography and molecular dynamics simulations. Here, we report the first cryo-EM structures of full-length, glycosylated, soluble sACE (sACE ). Both monomeric and dimeric forms of the highly flexible apo enzyme were reconstructed from a single dataset. The N- and C-terminal domains of monomeric sACE were resolved at 3.7 and 4.1 Å, respectively, while the interacting N-terminal domains responsible for dimer formation were resolved at 3.8 Å. Mechanisms are proposed for intradomain hinging, cooperativity, and homodimerization. Furthermore, the observation that both domains were in the open conformation has implications for the design of sACE modulators.

PubMed: 35818993
DOI: 10.15252/embj.2021110550

Experimental method

ELECTRON MICROSCOPY (4.34 Å)