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Cryo‐EM reveals mechanisms of angiotensin I‐converting enzyme allostery and dimerization

DOI: 10.15252/embj.2021110550 DOI Help

Authors: Lizelle Lubbe (University of Cape Town) , Bryan Trevor Sewell (University of Cape Town) , Jeremy D. Woodward (University of Cape Town) , Edward D. Sturrock (University of Cape Town)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: The Embo Journal , VOL 66

State: Published (Approved)
Published: July 2022
Diamond Proposal Number(s): 24039

Open Access Open Access

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 (sACES1211). 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 sACES1211 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.

Journal Keywords: angiotensin I-converting enzyme; cryo-electron microscopy; glycoprotein; homodimerization; zinc metalloprotease

Diamond Keywords: Cardiovascular Disease; Enzymes

Subject Areas: Biology and Bio-materials, Medicine

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios III-Titan Krios III at Diamond

Added On: 14/07/2022 10:10

Documents:
The EMBO Journal - 2022 - Lubbe - Cryo%E2%80%90EM reveals mechanisms of angiotensin I%E2%80%90converting enzyme allostery and dimerization.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)