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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

Alignment of lamprey ER with human ERα and human ERβ.α-helices and β-strands from the crystal structures of ERα and ERβ are shaded in each sequence and notated below the alignment. Residues in human ERα involved in binding of estradiol are shown in green. Glu-419, which stabilizes His-524 is shaded in brown. Crystal structure accessions are human ERα [PDB: 1G50], human ERβ [1QKM].
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pone-0006038-g002: Alignment of lamprey ER with human ERα and human ERβ.α-helices and β-strands from the crystal structures of ERα and ERβ are shaded in each sequence and notated below the alignment. Residues in human ERα involved in binding of estradiol are shown in green. Glu-419, which stabilizes His-524 is shaded in brown. Crystal structure accessions are human ERα [PDB: 1G50], human ERβ [1QKM].

Mentions: The 3D structure of human ERα [PDB: 1G50] was used as a template for constructing the 3D model of lamprey ER. The sequences of the steroid-binding domain of lamprey ER and human ERα are 57% identical without any gaps [Figure 2]. This strong similarity between lamprey ER and its template gives us confidence in the accuracy lamprey 3D model. We used the Multiple Mapping Method (MMM) software [16] to construct the 3D model of lamprey ER. We selected three alignment algorithms Muscle, Align2D and ClustalW to align the target sequence [lamprey ER] and the human ERα template [1G50]. MMM takes each alignment and constructs a composite alignment, which is then used by Modeller [17] to construct the 3D model of lamprey ER.


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

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

Alignment of lamprey ER with human ERα and human ERβ.α-helices and β-strands from the crystal structures of ERα and ERβ are shaded in each sequence and notated below the alignment. Residues in human ERα involved in binding of estradiol are shown in green. Glu-419, which stabilizes His-524 is shaded in brown. Crystal structure accessions are human ERα [PDB: 1G50], human ERβ [1QKM].
© Copyright Policy
Related In: Results  -  Collection

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

pone-0006038-g002: Alignment of lamprey ER with human ERα and human ERβ.α-helices and β-strands from the crystal structures of ERα and ERβ are shaded in each sequence and notated below the alignment. Residues in human ERα involved in binding of estradiol are shown in green. Glu-419, which stabilizes His-524 is shaded in brown. Crystal structure accessions are human ERα [PDB: 1G50], human ERβ [1QKM].
Mentions: The 3D structure of human ERα [PDB: 1G50] was used as a template for constructing the 3D model of lamprey ER. The sequences of the steroid-binding domain of lamprey ER and human ERα are 57% identical without any gaps [Figure 2]. This strong similarity between lamprey ER and its template gives us confidence in the accuracy lamprey 3D model. We used the Multiple Mapping Method (MMM) software [16] to construct the 3D model of lamprey ER. We selected three alignment algorithms Muscle, Align2D and ClustalW to align the target sequence [lamprey ER] and the human ERα template [1G50]. MMM takes each alignment and constructs a composite alignment, which is then used by Modeller [17] to construct the 3D model of lamprey ER.

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