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3D model of lamprey estrogen receptor with estradiol and 15alpha-hydroxy-estradiol.

Baker ME, Chang DJ, Chandsawangbhuwana C - PLoS ONE (2009)

Bottom Line: BLAST analysis of GenBank indicates that among vertebrate ERs, only lamprey ER contains a methionine at this position.Thus, the contact between Sdelta on Met-409 and 15alpha-OH-E2 is unique.Interestingly, BLAST finds that five New World monkeys and a sturgeon contain a valine instead of isoleucine.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of California San Diego, La Jolla, CA, USA. mbaker@ucsd.edu

ABSTRACT

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 15alpha-hydroxy-steroids are active steroids. For example, 15alpha-hydroxy-estradiol [15alpha-OH-E2] is the estrogen, instead of estradiol [E2]. To investigate how 15alpha-OH-E2 binds lamprey ER, we constructed a 3D model of the lamprey ER with E2 and 15alpha-OH-E2.

Methodology: We used the 3D structure of human ERalpha as a template to construct a 3D model of lamprey ER. E2 and 15alpha-OH-E2 were inserted into the 3D model of lamprey ER and 15alpha-OH-E2 was inserted into human ERalpha. 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 15alpha-OH-E2 shows that Sdelta on Met-409 can form a hydrogen bond with the 15alpha-hydroxyl on 15alpha-OH-E2. In human ERalpha, the corresponding residue Ile-424 has a van der Waals contact with 15alpha-OH-E2. BLAST analysis of GenBank indicates that among vertebrate ERs, only lamprey ER contains a methionine at this position. Thus, the contact between Sdelta on Met-409 and 15alpha-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.

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Related in: MedlinePlus

Interaction of 15α-OH-E2 with human ERα and the 3D model lamprey ER.A. In human ERα, Cγ2 on Ile-424 and Cε on Met-421 have van der Waals contacts with 15α-OH-E2. B. Lamprey ER has stabilizing interactions with the A ring of 15α-OH-E2 that are similar to those in human ERα. His-509 has rotated and does not form a hydrogen bond with the C17-hydroxyl on E2. Cδ2 on His-509 has a van der Waals contact with the C17-hydroxyl. Sδ on Met-406 and Met-409 stabilize 15α-OH-E2.
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pone-0006038-g005: Interaction of 15α-OH-E2 with human ERα and the 3D model lamprey ER.A. In human ERα, Cγ2 on Ile-424 and Cε on Met-421 have van der Waals contacts with 15α-OH-E2. B. Lamprey ER has stabilizing interactions with the A ring of 15α-OH-E2 that are similar to those in human ERα. His-509 has rotated and does not form a hydrogen bond with the C17-hydroxyl on E2. Cδ2 on His-509 has a van der Waals contact with the C17-hydroxyl. Sδ on Met-406 and Met-409 stabilize 15α-OH-E2.

Mentions: Figure 5A shows that the stabilizing interactions between 15α-OH-E2 and human ERα are similar to that shown in Figure 4A for E2 and human ERα. However, as found for E2 binding to human ERα and lamprey ER, there are important differences in the interaction between the D ring of 15α-OH-E2 and human ERα [Figure 5A] and lamprey ER [Figure 5B]. The 17β-hydroxyl on E2 still has favorable interactions with His-524, Met-343 and Leu-525 in human ERα. Also, Cε on Met-421 and Cγ2 on Ile-524 are 3.8 Å and 3.2 Å, respectively, from the 15α-hydroxyl on 15α-OH-E2. The backbone oxygen on Glu-419 is 3 Å from Nε2 of His-524, which stabilizes His-524.


3D model of lamprey estrogen receptor with estradiol and 15alpha-hydroxy-estradiol.

Baker ME, Chang DJ, Chandsawangbhuwana C - PLoS ONE (2009)

Interaction of 15α-OH-E2 with human ERα and the 3D model lamprey ER.A. In human ERα, Cγ2 on Ile-424 and Cε on Met-421 have van der Waals contacts with 15α-OH-E2. B. Lamprey ER has stabilizing interactions with the A ring of 15α-OH-E2 that are similar to those in human ERα. His-509 has rotated and does not form a hydrogen bond with the C17-hydroxyl on E2. Cδ2 on His-509 has a van der Waals contact with the C17-hydroxyl. Sδ on Met-406 and Met-409 stabilize 15α-OH-E2.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2698217&req=5

pone-0006038-g005: Interaction of 15α-OH-E2 with human ERα and the 3D model lamprey ER.A. In human ERα, Cγ2 on Ile-424 and Cε on Met-421 have van der Waals contacts with 15α-OH-E2. B. Lamprey ER has stabilizing interactions with the A ring of 15α-OH-E2 that are similar to those in human ERα. His-509 has rotated and does not form a hydrogen bond with the C17-hydroxyl on E2. Cδ2 on His-509 has a van der Waals contact with the C17-hydroxyl. Sδ on Met-406 and Met-409 stabilize 15α-OH-E2.
Mentions: Figure 5A shows that the stabilizing interactions between 15α-OH-E2 and human ERα are similar to that shown in Figure 4A for E2 and human ERα. However, as found for E2 binding to human ERα and lamprey ER, there are important differences in the interaction between the D ring of 15α-OH-E2 and human ERα [Figure 5A] and lamprey ER [Figure 5B]. The 17β-hydroxyl on E2 still has favorable interactions with His-524, Met-343 and Leu-525 in human ERα. Also, Cε on Met-421 and Cγ2 on Ile-524 are 3.8 Å and 3.2 Å, respectively, from the 15α-hydroxyl on 15α-OH-E2. The backbone oxygen on Glu-419 is 3 Å from Nε2 of His-524, which stabilizes His-524.

Bottom Line: BLAST analysis of GenBank indicates that among vertebrate ERs, only lamprey ER contains a methionine at this position.Thus, the contact between Sdelta on Met-409 and 15alpha-OH-E2 is unique.Interestingly, BLAST finds that five New World monkeys and a sturgeon contain a valine instead of isoleucine.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of California San Diego, La Jolla, CA, USA. mbaker@ucsd.edu

ABSTRACT

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 15alpha-hydroxy-steroids are active steroids. For example, 15alpha-hydroxy-estradiol [15alpha-OH-E2] is the estrogen, instead of estradiol [E2]. To investigate how 15alpha-OH-E2 binds lamprey ER, we constructed a 3D model of the lamprey ER with E2 and 15alpha-OH-E2.

Methodology: We used the 3D structure of human ERalpha as a template to construct a 3D model of lamprey ER. E2 and 15alpha-OH-E2 were inserted into the 3D model of lamprey ER and 15alpha-OH-E2 was inserted into human ERalpha. 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 15alpha-OH-E2 shows that Sdelta on Met-409 can form a hydrogen bond with the 15alpha-hydroxyl on 15alpha-OH-E2. In human ERalpha, the corresponding residue Ile-424 has a van der Waals contact with 15alpha-OH-E2. BLAST analysis of GenBank indicates that among vertebrate ERs, only lamprey ER contains a methionine at this position. Thus, the contact between Sdelta on Met-409 and 15alpha-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.

Show MeSH
Related in: MedlinePlus