3D Model of Lamprey Estrogen Receptor with Estradiol and 15α-Hydroxy-Estradiol

Background: Lamprey, basal vertebrate, is an important model system for understanding early events in vertebrate evolution. Lamprey contains orthologs of the estrogen receptor [ER], progesterone receptor and corticoid receptor. A perplexing property of lamprey is that 15 alpha-hydroxy-steroids are active steroids. For example, 15 alpha-hydroxy-estradiol [15 alpha-OH-E2] is the estrogen, instead of estradiol [E2]. To investigate how 15 alpha-OH-E2 binds lamprey ER, we constructed a 3D model of the lamprey ER with E2 and 15 alpha-OH-E2. Methodology: We used the 3D structure of human ER alpha as a template to construct a 3D model of lamprey ER. E2 and 15 alpha-OH-E2 were inserted into the 3D model of lamprey ER and 15 alpha-OH-E2 was inserted into human ERa. Then the each steroid-protein complex was refined using Discover 3 from Insight II software. To determine if lamprey ER had some regions that were unique among vertebrate ERs, we used the ligand-binding domain of lamprey ER as a query for a BLAST search of GenBank. Principal Findings: Our 3D model of lamprey ER with 15 alpha-OH-E2 shows that Sd on Met-409 can form a hydrogen bond with the 15 alpha-hydroxyl on 15 alpha-OH-E2. In human ER alpha, the corresponding residue Ile-424 has a van der Waals contact with 15 alpha-OH-E2. BLAST analysis of GenBank indicates that among vertebrate ERs, only lamprey ER contains a methionine at this position. Thus, the contact between S delta on Met-409 and 15 alpha-OH-E2 is unique. Interestingly, BLAST finds that five New World monkeys and a sturgeon contain a valine instead of isoleucine. Significance: In addition to shedding light on the structure of the ER in a basal vertebrate, our 3D model of lamprey ER should prove useful in virtual screening of chemical libraries to identify compounds for controlling reproduction in sea lamprey, an environmental pest in Lake Michigan.