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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

Structures of estradiol and 15α-hydroxy-estradiol.Estradiol is the biologically active estrogen in most vertebrates. 15α-hydroxy-estradiol is found in lamprey blood [11], [12] and may be the biologically active estrogen.
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pone-0006038-g001: Structures of estradiol and 15α-hydroxy-estradiol.Estradiol is the biologically active estrogen in most vertebrates. 15α-hydroxy-estradiol is found in lamprey blood [11], [12] and may be the biologically active estrogen.

Mentions: Lamprey and hagfish are two primitive fish at the base the vertebrate line, which has motivated studies of these fish to understand early events in vertebrate evolution [1]–[3]. In particular, sea lamprey (Petromyzon marinus) is of interest for understanding the origins of adrenal and sex steroid signaling [4]–[10] because orthologs of vertebrate estrogen receptor [ER], progesterone receptor [PR] and a corticoid receptor [CR] have been cloned from sea lamprey [7]. A puzzle about sea lamprey is that the principal estrogens, androgens and progestins in its serum differ from that in humans [11]–[14]. For example, lamprey serum contains 15α-hydroxy-estradiol [15α-OH-E2] and 15α-hydroxy-estrone [15α-OH-E1] and low levels of estradiol [E2], which is the main estrogen in land vertebrates and bony fish [Figure 1]. Lamprey serum also contains 15α-OH-progesterone and 15α-OH-testosterone and low levels of progesterone and testosterone. These data suggest that 15α-hydroxy-steroids are the active steroids in lamprey.


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

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

Structures of estradiol and 15α-hydroxy-estradiol.Estradiol is the biologically active estrogen in most vertebrates. 15α-hydroxy-estradiol is found in lamprey blood [11], [12] and may be the biologically active estrogen.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0006038-g001: Structures of estradiol and 15α-hydroxy-estradiol.Estradiol is the biologically active estrogen in most vertebrates. 15α-hydroxy-estradiol is found in lamprey blood [11], [12] and may be the biologically active estrogen.
Mentions: Lamprey and hagfish are two primitive fish at the base the vertebrate line, which has motivated studies of these fish to understand early events in vertebrate evolution [1]–[3]. In particular, sea lamprey (Petromyzon marinus) is of interest for understanding the origins of adrenal and sex steroid signaling [4]–[10] because orthologs of vertebrate estrogen receptor [ER], progesterone receptor [PR] and a corticoid receptor [CR] have been cloned from sea lamprey [7]. A puzzle about sea lamprey is that the principal estrogens, androgens and progestins in its serum differ from that in humans [11]–[14]. For example, lamprey serum contains 15α-hydroxy-estradiol [15α-OH-E2] and 15α-hydroxy-estrone [15α-OH-E1] and low levels of estradiol [E2], which is the main estrogen in land vertebrates and bony fish [Figure 1]. Lamprey serum also contains 15α-OH-progesterone and 15α-OH-testosterone and low levels of progesterone and testosterone. These data suggest that 15α-hydroxy-steroids are the active steroids in lamprey.

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