PMID- 16990645
OWN - NLM
STAT- MEDLINE
DCOM- 20070125
LR  - 20210217
IS  - 0022-2275 (Print)
IS  - 0022-2275 (Linking)
VI  - 47
IP  - 12
DP  - 2006 Dec
TI  - Modeling the structure of the StART domains of MLN64 and StAR proteins in complex 
      with cholesterol.
PG  - 2614-30
AB  - Steroidogenic acute regulatory protein-related lipid transfer (StART) domains are 
      ubiquitously involved in intracellular lipid transport and metabolism and other 
      cell-signaling events. In this work, we use a flexible docking algorithm, 
      comparative modeling, and molecular dynamics (MD) simulations to generate 
      plausible three-dimensional atomic models of the StART domains of human 
      metastatic lymph node 64 (MLN64) and steroidogenic acute regulatory protein 
      (StAR) proteins in complex with cholesterol. Our results show that cholesterol 
      can adopt a similar conformation in the binding cavity in both cases and that the 
      main contribution to the protein-ligand interaction energy derives from 
      hydrophobic contacts. However, hydrogen-bonding and water-mediated interactions 
      appear to be important in the fine-tuning of the binding affinity and the 
      position of the ligand. To gain insights into the mechanism of binding, we 
      carried out steered MD simulations in which cholesterol was gradually extracted 
      from within the StAR model. These simulations indicate that a transient opening 
      of loop Omega1 may be sufficient for uptake and release, and they also reveal a 
      pathway of intermediate states involving residues known to be crucial for StAR 
      activity. Based on these observations, we suggest specific mutagenesis targets 
      for binding studies of cholesterol and its derivatives that could improve our 
      understanding of the structural determinants for ligand binding by sterol carrier 
      proteins.
FAU - Murcia, Marta
AU  - Murcia M
AD  - Department of Physiology and Biophysics, Weill Medical College of Cornell 
      University, New York, NY 10021, USA.
FAU - Faraldo-Gomez, Jose D
AU  - Faraldo-Gomez JD
FAU - Maxfield, Frederick R
AU  - Maxfield FR
FAU - Roux, Benoit
AU  - Roux B
LA  - eng
SI  - PDB/2I92
SI  - PDB/2I93
GR  - DK-27083/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20060921
PL  - United States
TA  - J Lipid Res
JT  - Journal of lipid research
JID - 0376606
RN  - 0 (Carrier Proteins)
RN  - 0 (Ligands)
RN  - 0 (Membrane Proteins)
RN  - 0 (Phosphoproteins)
RN  - 0 (STARD3 protein, human)
RN  - 0 (steroidogenic acute regulatory protein)
RN  - 97C5T2UQ7J (Cholesterol)
SB  - IM
MH  - Algorithms
MH  - Binding Sites
MH  - Carrier Proteins/*chemistry/*metabolism
MH  - Cholesterol/chemistry/*metabolism
MH  - Humans
MH  - Hydrogen Bonding
MH  - Hydrophobic and Hydrophilic Interactions
MH  - In Vitro Techniques
MH  - Ligands
MH  - Membrane Proteins/*chemistry/*metabolism
MH  - Models, Molecular
MH  - Molecular Conformation
MH  - Phosphoproteins/*chemistry/*metabolism
MH  - Protein Binding
MH  - Protein Conformation
MH  - Protein Structure, Tertiary
MH  - Thermodynamics
EDAT- 2006/09/23 09:00
MHDA- 2007/01/26 09:00
CRDT- 2006/09/23 09:00
PHST- 2006/09/23 09:00 [pubmed]
PHST- 2007/01/26 09:00 [medline]
PHST- 2006/09/23 09:00 [entrez]
AID - S0022-2275(20)43254-7 [pii]
AID - 10.1194/jlr.M600232-JLR200 [doi]
PST - ppublish
SO  - J Lipid Res. 2006 Dec;47(12):2614-30. doi: 10.1194/jlr.M600232-JLR200. Epub 2006 
      Sep 21.