Introduction¹

The physiological effects of progestins are mediated by the progesterone receptor, a member of the steroid/nuclear receptor superfamily. As progesterone is required for maintenance of pregnancy, its receptor has been a target for pharmaceuticals. The nature of this structure explains the receptor's selective affinity for progestins and establishes a common mode of recognition of 3-oxy steroids by the cognate receptors. Although the overall fold of the progesterone receptor is similar to that found in related receptors, the progesterone receptor has a quite different mode of dimerization. A hormone-induced stabilization of the carboxy-terminal secondary structure of the ligand-binding domain of the progesterone receptor accounts for the stereochemistry of this distinctive dimer, explains the receptor's characteristic pattern of ligand-dependent protease resistance and its loss of repression, and indicates how the anti-progestin RU486 might work in birth control. The structure also indicates that the analogous 3-keto-steroid receptors may have a similar mechanism of action.

Binding Domains

Where is the active site?

Let's take a closer look at the active site

There are three hydrogen bond donors that bond to the  3-keto group of progesterone

1. The side chain amido NH2 group of Gln 725 donates a hydrogen bond to the 3-keto group of progesterone.
2. The side chain amido NH2 group of Arg 766 also donates a hydrogen bond to the 3-keto group.                                                     
3. Another amido NH2 group of Arg 766 donates a hydrogen bond ( through a fixed water site) to the amido oxygen of Gln 725, which stablaizes the required orientation of Gln 725.   This fixed water is the third H-bond donor to the 3-keto group of progesterone, which lends both specificity and rigidity to the network.

The the orientaion of the highly flexible Arg 766 is fixed by a hydrogen bond between the hydrogen of the secondary amine of Arg 766 to the carbonyl of Try 777.

The required position and orientation of the Gln 725 amido group is buttressed (through an intervining fixed water site) by the backbone carbonyl of Phe 778.

We can color the other amino acids that have van der Waal interactions with the ligand.  

Protein Characteristics

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   1 GQDIQLIPPL INLLMSIEPD VIYAGHDNTK PDTSSSLLTS LNQLGERQLL 
           S HH HHHHHHHS           SS    HHHHHHH HHHHHHHHHH 

  51 SVVKWSKSLP GFRNLHIDDQ ITLIQYSWMS LMVFGLGWRS YKHVSGQMLY 
     HHHHHHHHTT TGGGS HHHH HHHHHHHTHH HHHHHHHHHH HHHHTTSSEE 

 101 FAPDLILNEQ RMKESSFYSL CLTMWQIPQE FVKLQVSQEE FLCMKVLLLL 
     SBTTEEE GG G  SHHHHHH HHHHHTHHHH HHHHT  HHH HHHHHHHHHT 

 151 NTIPLEGLRS QTQFEEMRSS YIRELIKAIG LRQKGVVSSS QRFYQLTKLL 
     SEEETTTTTT HHHHHHHHHH HHHHHHHHHH TT  STTHHH HHHHHHHHHH 

 201 DNLHDLVKQL HLYCLNTFIQ SRALSVEFPE MMSEVIAAQL PKILAGMVKP 
     HHHHHHHHHH HHHHHHHHHT HHHHT    H HHHHHHHHHT HHHHTT EEE 

 251 LLFHKK 
       S  

   1 GQDIQLIPPL INLLMSIEPD VIYAGHDNTK PDTSSSLLTS LNQLGERQLL 
             HH HHHHHHT            SS    HHHHHHH HHHHHHHHHH 

  51 SVVKWSKSLP GFRNLHIDDQ ITLIQYSWMS LMVFGLGWRS YKHVSGQMLY 
     HHHHHHHHTT TGGGS HHHH HHHHHHHTHH HHHHHHHHHH HHHSTTSEEE 

 101 FAPDLILNEQ RMKESSFYSL CLTMWQIPQE FVKLQVSQEE FLCMKVLLLL 
     SBTTEEEEHH HHHTSS HHH HHHHHTHHHH HHHHT  HHH HHHHHHHHHT 

 151 NTIPLEGLRS QTQFEEMRSS YIRELIKAIG LRQKGVVSSS QRFYQLTKLL 
     SEE TTTTTT HHHHHHHHHH HHHHHHHHHH HH  SHHHHH HHHHHHHHHH 

 201 DNLHDLVKQL HLYCLNTFIQ SRALSVEFPE MMSEVIAAQL PKILAGMVKP 
     HHHHHHHHHH HHHHHHHHHT HHHHT    H HHHHHHHHHT HHHHTT SEE 

 251 LLFHKK