Modeling human neurokinin-1 receptor structure using the crystal structure of bovine rhodopsin

Khedkar, Santosh A., Malde, Alpeshkumar K. and Coutinho, Evans C. (2005) Modeling human neurokinin-1 receptor structure using the crystal structure of bovine rhodopsin. Internet Electronic Journal of Molecular Design, 4 5: 329-341.

Attached Files (Some files may be inaccessible until you login with your UQ eSpace credentials)
Name Description MIMEType Size Downloads
UQ162292_OA.pdf Full text (open access) application/pdf 836.17KB 1
Author Khedkar, Santosh A.
Malde, Alpeshkumar K.
Coutinho, Evans C.
Title Modeling human neurokinin-1 receptor structure using the crystal structure of bovine rhodopsin
Journal name Internet Electronic Journal of Molecular Design
ISSN 1538-6414
Publication date 2005-05
Sub-type Article (original research)
Open Access Status File (Publisher version)
Volume 4
Issue 5
Start page 329
End page 341
Total pages 13
Editor Ovidiu Ivanciuc
Place of publication Galveston, TX, United States
Publisher BioChem Press
Language eng
Subject 030402 Biomolecular Modelling and Design
Formatted 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status Non-UQ
Additional Notes Proceedings of the Internet Electronic Conference of Molecular Design 2004 IECMD 2004, November 29 – December 12, 2004.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Chemistry and Molecular Biosciences
Version Filter Type
Citation counts: Google Scholar Search Google Scholar
Created: Fri, 30 Jan 2009, 11:39:55 EST by Sophie Jordan on behalf of School of Chemistry & Molecular Biosciences