Cryo-EM reveals mechanisms of angiotensin I-converting enzyme allostery and dimerization
Lizelle Lubbe1, Bryan Trevor Sewell1,2, Jeremy D Woodward2
1Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
Insights
The first cryo-EM structures of full-length, glycosylated somatic angiotensin I-converting enzyme (sACE) reveal its monomeric and dimeric forms. These findings provide new insights into sACE structure and flexibility for designing novel therapeutics.
Area of Science:
- Biochemistry
- Structural Biology
- Cardiovascular Research
Background:
- Hypertension is a major cardiovascular disease risk factor, with ACE inhibitors being key treatments.
- Limited understanding of somatic angiotensin I-converting enzyme (sACE) structure hinders drug development.
- Previous studies used truncated sACE forms, lacking insights into full-length enzyme behavior.
Purpose of the Study:
- To determine the cryo-electron microscopy (cryo-EM) structures of full-length, glycosylated, soluble sACE (sACES1211).
- To investigate the structural mechanisms of sACE monomerization, dimerization, and flexibility.
- To provide a structural basis for designing improved sACE modulators.
Main Methods:
- Cryo-electron microscopy (cryo-EM) for high-resolution structure determination.
- Reconstruction of both monomeric and dimeric sACE forms from a single dataset.
- Analysis of domain interactions and conformational flexibility.
Main Results:
- First cryo-EM structures of full-length, glycosylated sACE (sACES1211) obtained.
- Both monomeric and dimeric sACE forms were resolved, revealing distinct domain structures.
- Proposed mechanisms for intradomain hinging, cooperativity, and homodimerization.
Conclusions:
- The structures reveal highly flexible monomeric and dimeric sACE states.
- Observed open conformations of sACE domains offer new targets for drug design.
- These findings advance the understanding of sACE regulation and inhibition strategies.
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.
Related Concept Videos
01:30Antihypertensive Drugs: Angiotensin-Converting Enzyme Inhibitors
01:28Cryo-electron Microscopy
01:25Antihypertensive Drugs: Direct Renin Inhibitors
01:26Heart Failure Drugs: Inhibitors of Renin-Angiotensin System
01:58Cooperative Allosteric Transitions
01:19Allosteric Proteins-ATCase
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...