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ABSTRACT: Sea lamprey, a basal vertebrate, contains a progesterone receptor [PR]. An unusual property of lamprey is that gonadotropin-releasing hormone induces synthesis of 15α-hydroxy-progesterone [15α-OH-P] instead of progesterone. There also is indirect evidence for 7α-OH-P in lamprey serum. To determine if there is a structural basis for the binding of 7α-OH-P and 15α-OH-P to lamprey PR, we constructed 3D models of the lamprey PR complexed with progesterone, 7α-OH-P and 15α-OH-P. These 3D models reveal that Met-277 in lamprey PR has a specific interaction with the 15α-hydroxyl on 15α-OH-P and with Met-192, which also contacts the 15α-hydroxyl group. We also find that 7α-OH-P has favorable contacts with side-chains in lamprey PR. BLAST searches reveal that Met-277 on lamprey PR is unique among vertebrate PRs. This unique site on lamprey PR could be a target for compounds to control reproduction in sea lamprey, an environmental pest in Lake Michigan.
Steroids 11/2010; 76(1-2):169-76. · 2.83 Impact Factor
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ABSTRACT: The origins of signaling by vertebrate steroids are not fully understood. An important advance was the report that an estrogen-binding steroid receptor [SR] is present in amphioxus, a basal chordate with a similar body plan as vertebrates. To investigate the evolution of estrogen-binding to steroid receptors, we constructed a 3D model of amphioxus SR complexed with estradiol. This 3D model indicates that although the SR is activated by estradiol, some interactions between estradiol and human ERalpha are not conserved in the SR, which can explain the low affinity of estradiol for the SR. These differences between the SR and ERalpha in the steroid-binding domain are sufficient to suggest that another steroid is the physiological regulator of the SR. The 3D model predicts that mutation of Glu-346 to Gln will increase the affinity of testosterone for amphioxus SR and elucidate the evolution of steroid-binding to nuclear receptors.
Biochemical and Biophysical Research Communications 07/2009; 386(3):516-20. · 2.48 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
PLoS ONE 02/2009; 4(6):e6038. · 4.09 Impact Factor
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ABSTRACT: Lamprey, a basal vertebrate, 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. Our 3D model shows that S[delta] 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. 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 the Great Lakes in the USA.
Nature Precedings.
