Cryo-EM reveals mechanisms of angiotensin I-converting enzyme allostery and dimerization.
Lizelle LubbeBryan Trevor SewellJeremy D WoodwardEdward D SturrockPublished in: The EMBO journal (2022)
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 S1211 ). 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 S1211 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.
Keyphrases
- blood pressure
- molecular dynamics simulations
- cardiovascular disease
- hypertensive patients
- angiotensin converting enzyme
- angiotensin ii
- heart rate
- high resolution
- type diabetes
- molecular docking
- small molecule
- minimally invasive
- blood glucose
- cardiovascular risk factors
- computed tomography
- dna methylation
- magnetic resonance
- cardiovascular events
- glycemic control
- insulin resistance
- contrast enhanced