Structural and Functional Insights into Aldosterone Synthase Interaction with Ligands and Redox Partner Proteins for Enhanced Treatment of Hypertension

Abstract

Primary aldosteronism is the most common form of secondary hypertension and is often associated with cardiac disease. Primary aldosteronism develops due to excessive amounts of the steroid hormone aldosterone, the most potent human mineralocorticoid. Aldosterone synthesized by cytochrome P450 11B2 (CYP11B2, aldosterone synthase) regulates blood pressure and mineral homeostasis. CYP11B2 is 93% identical to the cortisol‐producing CYP11B1. As a result, treatment of aldosterone‐derived hypertension is impeded due to the lack of drugs specifically targeting CYP11B2.Herein a structure/function approach was used to examine CYP11B2 interaction with both 1) drugs and 2) its redox partner protein adrenodoxin. First, the X‐ray structure of CYP11B2 was determined with the drug LCI699. LCI699 was initially developed as CYP11B2 inhibitor but is now the first drug in clinical trials for the treatment of Cushing’s disease as an inhibitor of CYP11B1. LCI699 positioning in the CYP11B2 active site and comparison with similar compounds in CYP11B1 provides valuable clues for enhanced design of drugs for both enzymes. The second half of this study is focused on CYP11B2 interaction with its redox partner protein adrenodoxin. Studies revealed that adrenodoxin promotes CYP11B2 binding of its physiological substrate 11‐deoxycorticosterone and an adrenodoxin/CYP11B2 fusion protein was generated to examine the protein/protein interaction. An X‐ray structure of this complex identified the adrenodoxin binding site on the proximal face of CYP11B2 and specific interactions. Overall these studies improve our understanding of the aldosterone biosynthetic system and support the design of selective drugs for primary aldosteronism.Support or Funding InformationThe research was funded by a postdoctoral fellowship from the American Heart Association (19POST34430199, SBA) and startup funds from the University of Michigan (EES).