1 / 6

Bioinformatics and molecular modeling studies of membrane proteins

Shiva Amiri Professor Mark S.P. Sansom June 11, 2004. Bioinformatics and molecular modeling studies of membrane proteins. Membrane proteins. sdf. constitute approximately 25% of the genome important drug targets - nerve and muscle excitation - hormonal secretion - sensory transduction

shania
Download Presentation

Bioinformatics and molecular modeling studies of membrane proteins

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Shiva Amiri Professor Mark S.P. Sansom June 11, 2004 Bioinformatics and molecular modeling studies of membrane proteins

  2. Membrane proteins sdf • constitute approximately 25% of the genome • important drug targets - nerve and muscle excitation - hormonal secretion - sensory transduction - control of salt and water balance etc. • malfunctions result in various diseases • difficult to get their structures Ligand gated ion channels (LGICs) • function is dependent upon the binding of a ligand. • examples of LGICs: nAChR, GABAA and GABAC receptors, 5HT3 receptor, Glycine receptor Sperelakis, N., Cell Physiology Source Book

  3. My project • to take available structural data and put the pieces together • main focus so far: using available information to predict the structure and motions of the α-7 nicotinic acetylcholine receptor (nAChR) we have: 4Å cryo-EM structure of AChR transmembrane domain 2.7Å crystal structure of ligand binding domain homolog task: to combine the separate domains • the use of bioinformatics and simulation tools to study functionally relevant motions of LGICs TM LB LB M3 M2 M4 M1 TM

  4. The process … homology modelling -Modeller, Procheck {θmax, zmax} 2 PDBs ZAlign termini distances bad contacts ( Unwin distances ) analysis – xfarbe plots make model using chosen {θ, z} GROMACS energy minimization procheck motion analysis: GNM CONCOORD electrostatics (Kaihsu Tai) pore dimensions - HOLE homology models of other LGICs

  5. Course grain methods of motion analysis • Gaussian network model (GNM) • a course-grained model to approximate fluctuations of residues • information on the flexibility and function of the protein • produces theoretical B-values • CONCOORD • LB region spikes rotating to one side and the TM spikes rotating in the opposite direction, suggesting a twisting motion of the receptor

  6. Summary Future work • modeling methods for LGICs • predicted structure of α-7 nAChR • used various methods (GNM, CONCOORD) to look at motions of the predicted structure of α-7 nAChR • models of anionic LGICs (GABA and glycine) using current α-7 nAChR structure • models of other LGICs • motion analysis of other LGICs • looking at the hydrophobic girdle (M2) of LGICs to study patterns of conservation and the behaviour of these residues during gating • simulation studies of constructed models

More Related