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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. May 2005, Volume 4, Number 5, 329-341 |
Modeling Human Neurokinin-1 Receptor Structure Using the
Crystal Structure of Bovine Rhodopsin
Santosh A. Khedkar, Alpeshkumar K. Malde, and Evans C. Coutinho
Internet Electron. J. Mol. Des. 2005, 4, 329-341
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Abstract:
G protein-coupled receptors (GPCRs) regulate a wide range of
physiological processes by transmitting signals to cells in response to
stimuli such as light, Ca2+ ions, odorants, amino acids, nucleotides,
peptides or proteins. GPCRs are by far the most successful drug
targets as evidenced by the fact that 50% of the marketed drugs treat
diseases by targeting nearly 20 GPCRs. The lack of high-resolution
structures of GPCRs limits the application of structure-based drug
design on these targets. However, the recent publication of the
crystal structure of bovine rhodopsin has changed the scenario in
GPCR structure modeling. Neurokinin-1 receptor (NK1R) is a
member of the family A of GPCR, which on modulation by
substance P (SP), produces a variety of physiological and
pathophysiological conditions. A high-resolution structure of NK1R
is not yet available and hence alternative approaches must be used
for building a model 3D-structure of the NK1 receptor, which can
then be used for structure-based drug design. We have constructed a
3D-structure of the NK1 receptor using the recently published high-resolution
crystal structure of bovine rhodopsin (PDB code: 1L9H)
with the Homology module in INSIGHT II. Due to the low sequence
identity between the target and reference proteins in the 7 TM
regions, a segmented approach for model building was used. The
loop and end regions were modeled using simulated annealing and
stringent energy minimization protocols. The model retains the
global arrangement of the GPCRs and is energetically and
geometrically consistent. The loops in the NK1R model are longer
than those in rhodopsin and their orientation in the model, in
particular the extracellular loops, would be of use in structure based
drug design studies. The lipophilic potential surface of the final
NK1R model has been calculated and reflects the characteristics of
this membrane protein. Earlier models built for the NK1 receptor
were only partial with several crucial elements missing. This work
provides a first complete model of human NK1R enabling ligand-GPCR
interactions to be investigated at the atomic level.
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