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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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Interaction of E2 with human ERα and the 3D model lamprey ER.A. Interaction between E2 and human ERα. B. Interaction between E2 and the 3D model of lamprey ER. Lamprey ER has stabilizing interactions with the A ring of E2 similar to those in human ERα. His-509 has rotated and does not have a hydrogen bond with the C17-hydroxyl on E2. Instead, Cδ2 has a van der Waals contact with the C17-hydroxyl on E2. Also, Cε and Sδ on Met-409 have stabilizing contacts with C15 on E2.
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pone-0006038-g004: Interaction of E2 with human ERα and the 3D model lamprey ER.A. Interaction between E2 and human ERα. B. Interaction between E2 and the 3D model of lamprey ER. Lamprey ER has stabilizing interactions with the A ring of E2 similar to those in human ERα. His-509 has rotated and does not have a hydrogen bond with the C17-hydroxyl on E2. Instead, Cδ2 has a van der Waals contact with the C17-hydroxyl on E2. Also, Cε and Sδ on Met-409 have stabilizing contacts with C15 on E2.

Mentions: Figure 3 shows that our 3D model of lamprey ER and the crystal structure of human ERα overlap nicely. The root mean square deviation [RMSD] of their Cα chains is 1.4 Å. In Figure 4A and 4B, we show the interaction of E2 with eight residues from human ERα and lamprey ER. Previous analyses have shown that these residues stabilize E2 in human ER [18]–[20]. Three of these amino acids, Arg-394, Glu-353 and Phe-404 in human ERα, correspond to functionally important residues in the PR [21], GR [22], AR [23] and MR [24], [25]. These steroid receptors contain corresponding arginine and phenylalanine residues, and a glutamine, which is a conservative replacement of glutamic acid.


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

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

Interaction of E2 with human ERα and the 3D model lamprey ER.A. Interaction between E2 and human ERα. B. Interaction between E2 and the 3D model of lamprey ER. Lamprey ER has stabilizing interactions with the A ring of E2 similar to those in human ERα. His-509 has rotated and does not have a hydrogen bond with the C17-hydroxyl on E2. Instead, Cδ2 has a van der Waals contact with the C17-hydroxyl on E2. Also, Cε and Sδ on Met-409 have stabilizing contacts with C15 on E2.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0006038-g004: Interaction of E2 with human ERα and the 3D model lamprey ER.A. Interaction between E2 and human ERα. B. Interaction between E2 and the 3D model of lamprey ER. Lamprey ER has stabilizing interactions with the A ring of E2 similar to those in human ERα. His-509 has rotated and does not have a hydrogen bond with the C17-hydroxyl on E2. Instead, Cδ2 has a van der Waals contact with the C17-hydroxyl on E2. Also, Cε and Sδ on Met-409 have stabilizing contacts with C15 on E2.
Mentions: Figure 3 shows that our 3D model of lamprey ER and the crystal structure of human ERα overlap nicely. The root mean square deviation [RMSD] of their Cα chains is 1.4 Å. In Figure 4A and 4B, we show the interaction of E2 with eight residues from human ERα and lamprey ER. Previous analyses have shown that these residues stabilize E2 in human ER [18]–[20]. Three of these amino acids, Arg-394, Glu-353 and Phe-404 in human ERα, correspond to functionally important residues in the PR [21], GR [22], AR [23] and MR [24], [25]. These steroid receptors contain corresponding arginine and phenylalanine residues, and a glutamine, which is a conservative replacement of glutamic acid.

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