PMID- 15976031
OWN - NLM
STAT- MEDLINE
DCOM- 20050912
LR  - 20190108
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 102
IP  - 27
DP  - 2005 Jul 5
TI  - Structural and biochemical basis for selective repression of the orphan nuclear 
      receptor liver receptor homolog 1 by small heterodimer partner.
PG  - 9505-10
AB  - The functional interaction between the orphan nuclear receptors small heterodimer 
      partner (SHP) and liver receptor homolog 1 (LRH-1), where SHP binds to LRH-1 and 
      represses its constitutive transcriptional activity, is crucial for regulating 
      genes involved in cholesterol homeostasis. Here, we report structural and 
      biochemical analyses of the LRH-1/SHP interaction. The crystal structure and 
      modeling studies of the LRH-1 ligand-binding domain bound to either of the two 
      LXXLL-related motifs of SHP show that the receptor undergoes conformational 
      changes to accommodate the SHP docking and reveal key residues that determine the 
      potency and selectivity of SHP binding. Through a combination of mutagenesis and 
      binding studies, we demonstrate that only the second SHP LXXLL motif is required 
      for repressing LRH-1, and this motif displays a strong preference for binding to 
      LRH-1 over the closely related receptor steroidogeneic factor 1 (SF-1). 
      Structural comparisons indicate that this binding selectivity is determined by 
      residues flanking the core LXXLL motifs. These results establish a structural 
      model for understanding how SHP interacts with LRH-1 to regulate cholesterol 
      homeostasis and provide new insights into how nuclear receptor/coregulator 
      selectivity is achieved.
FAU - Li, Yong
AU  - Li Y
AD  - Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick 
      Avenue, Grand Rapids, MI 49503, USA.
FAU - Choi, Mihwa
AU  - Choi M
FAU - Suino, Kelly
AU  - Suino K
FAU - Kovach, Amanda
AU  - Kovach A
FAU - Daugherty, Jennifer
AU  - Daugherty J
FAU - Kliewer, Steven A
AU  - Kliewer SA
FAU - Xu, H Eric
AU  - Xu HE
LA  - eng
SI  - PDB/1ZH7
GR  - U19 DK062434/DK/NIDDK NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
DEP - 20050623
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Nr5a2 protein, mouse)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (nuclear receptor subfamily 0, group B, member 2)
RN  - 97C5T2UQ7J (Cholesterol)
SB  - IM
MH  - Amino Acid Motifs/genetics
MH  - Animals
MH  - Cholesterol/metabolism
MH  - Crystallography
MH  - Gene Expression Regulation/*physiology
MH  - Homeostasis/*physiology
MH  - Mice
MH  - *Models, Molecular
MH  - Mutagenesis
MH  - Plasmids/genetics
MH  - Protein Binding
MH  - Receptors, Cytoplasmic and Nuclear/genetics/*metabolism
MH  - Transfection
PMC - PMC1157103
EDAT- 2005/06/25 09:00
MHDA- 2005/09/13 09:00
PMCR- 2005/07/05
CRDT- 2005/06/25 09:00
PHST- 2005/06/25 09:00 [pubmed]
PHST- 2005/09/13 09:00 [medline]
PHST- 2005/06/25 09:00 [entrez]
PHST- 2005/07/05 00:00 [pmc-release]
AID - 0501204102 [pii]
AID - 01029505 [pii]
AID - 10.1073/pnas.0501204102 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9505-10. doi: 
      10.1073/pnas.0501204102. Epub 2005 Jun 23.