Abstract
Progesterone receptor (PR), a member of nuclear receptor (NR) superfamily, plays a vital role for female reproductive tissue development, differentiation and maintenance. PR ligand, such as progesterone, induces conformation changes in PR ligand binding domain (LBD), thus mediates subsequent gene regulation cascades. PR LBD may adopt different conformations upon an agonist or an antagonist binding. These different conformations would trigger distinct transcription events. Therefore, the dynamics of PR LBD would be of general interest to biologists for a deep understanding of its structure-function relationship. However, no apo-form (non-ligand bound) of PR LBD model has been proposed either by experiments or computational methods so far. In this study, we explored the structural dynamics of PR LBD using molecular dynamics simulations and advanced sampling tools in both ligand-bound and the apo-forms. Resolved by the simulation study, helix 11, helix 12 and loop 895–908 (the loop between these two helices) are quite flexible in antagonistic conformation. Several residues, such as Arg899 and Glu723, could form salt-bridging interaction between helix 11 and helix 3, and are important for the PR LBD dynamics. And we also propose that helix 12 in apo-form PR LBD, not like other NR LBDs, such as human estrogen receptor α (ERα) LBD, may not adopt a totally extended conformation. With the aid of umbrella sampling and metadynamics simulations, several stable conformations of apo-form PR LBD have been sampled, which may work as critical structural models for further large scale virtual screening study to discover novel PR ligands for therapeutic application.
Highlights
Progesterone receptor (PR) is a member of the nuclear receptor (NR) superfamily, which regulates a complex network of gene transcription [1]
The major difference is that PR-A lacks the 164 amino acids that are presented in PR-B at its N-terminus [2,4,5]
We suggest that helix 12 in apo-form PR ligand binding domain (LBD) may not adopt the extended configuration as in other NR LBDs, such as retinoic X receptor-α (RXRα) LBD and estrogen receptor α (ERα) LBD
Summary
Progesterone receptor (PR) is a member of the nuclear receptor (NR) superfamily, which regulates a complex network of gene transcription [1]. Human PR is encoded by the PRG gene, which uses two promoters to express different gene products, PR-B and PR-A. These two PR isoforms (PR-B and PR-A) are almost identical within their DBD and LBD sequences where there are two activation function (AF1 and AF2) regions. The NTD in PR-B contains another activation function (AF3) which may enable PR-B to work as a much stronger transcription factor revealed in the cell experiment and mouse model [6,7]. More recent studies showed that the two isoforms contribute differently to the progress of breast cancer [10], and the ratio of PR-A and PR-B could regulate the mammary gland stem cell population in mouse model [11]. The underlying mechanisms of the distinct roles of the two isoforms still remain unrevealed
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