User:Harish Srinivas: Difference between revisions

='''Structural Features'''=

One cluster of core contacts links transmembrane '''(TM) I, II, and VII, cluster 1''' consists of individual interaction groups.  '''The second cluster''' of interactions links '''TM II, III, and IV''' through a series of four interaction groups  and a frequently observed interaction between position  interact through a hydrogen bond between an Asn  or Ser  and the indole nitrogen of a Trp. '''A third cluster''' of conserved contacts links together TM helices III, VI, and VII in the vicinity of the S1P1 receptor ligand binding pocket. These positions maintain important contacts between '''TM VI and TM III''' through two side chain-mediated interactions.  Finally, '''cluster number four''' consists of three interactions that constrain '''TM V relative to TM III and one interaction between TM V and TM VI.'''

The extracellular region for all GPCRs consists of three loops: '''ECL1 between TM helices II and III, ECL2 between TM helices IV and V, and ECL3 between TM helices VI and VII.''' Optionally, there is a '''structured N-terminus''' that interacts with the ECLs. In the case of S1P1 receptor the structured N-terminus '''occludes the binding pocket,''' in the '''antagonist-bound state,''' cutting off access to the extracellular environment.  One possible role for this structured N-terminus is that it is a feature of the S1P1 receptor structure in general and its presence implies the '''ligand does not access the binding pocket from the extracellular space directly.''' Instead, it is possible that the ligand gains access to the binding pocket through the lipid membrane where there is an '''enlarged gap between TM I and TM VI.''' This gap is '''larger in the S1P1 receptor''' than other class A GPCRs largely due to a '''shift in the position of the extracellular end of TM I away from TM VII''' in the S1P1 receptor.  

The S1P1 receptor provides '''18 residues''' from the transmembrane region for interactions with the ML056 antagonist along with '''three additional residues from ECL2 and two from the N-terminus.''' ML056 lies in an '''amphipathic pocket''' where the head group phosphonate interactions are largely polar in nature and the alkyl chain tail interactions are largely hydrophobic as would be expected. The polar interactions observed for ML056 largely confirm '''mutagenesis''' data establishing the importance of '''Arg120 and Glu121''' which were identified as important residues for '''supplying interactions with the zwitterionic sphingosine head group'''.  In addition, the phosphonate head group of ML056 is surrounded by a ring of positively charged and '''polar residues contributed by TM helices III and VII, ECL2, and the N-terminal capping helix.''' Together these residues form a pocket that provides charge complementarity and high-affinity interactions to the phosphate group of the sphingolipids.  A feature of ML056 is a '''primary amine''' located in the beta position relative to the phosphonate group. This primary amine is likely '''protonated''' and charged at physiological pH, thus enhancing its interactions with '''Glu121''' through '''salt bridge formation'''. In addition to '''Glu121, Asn101 and Tyr98''' provide '''hydrogen bonding interactions''' with the primary amine and amide linkage of ML056, respectively.  The '''phenyl aryl tail''' of ML056 inserts into a hydrophobic pocket consisting of residues from TM '''helices III, V, VI, and VII, as well as ECL2'''. The pocket is lined with short aliphatic residues that define the shape and hydrophobicity of the pocket and four aromatic residues that provide the potential for specific interactions.  

Ligands that bind to S1P1 function either as an agonist or antagonist based on minor differences in their structures, which translates to activating/deactivating shifts in critical receptor residues. Overall, the activating effect of a ligand on S1P1 is dependent on the '''length and position of its acyl chain''' in the ligand-binding pocket with respect to its '''amine and phosphate/phosphonate headgroup'''. Interestingly, the S1P1 structure shows that the antagonist ML056 is entirely in its meta conformation. Hanson and colleagues observed that '''switching the conformation pattern''' from meta to para switches the ligand effect from '''antagonism to agonism.''' In addition to the conformation of ligand, the volume of the ligand-binding pocket that is occupied also plays a critical role in receptor activation. An '''increase in length of the acyl chain''' of a ligand effectively '''switches its effect from antagonism to agonism.''' ML056 variants extending the acyl chain '''up to three additional methylenes''' can be accommodated in the binding pocket with no significant side chain shifts. However, once the total number of methylenes in the acyl chain reaches '''10''' (i.e. ML056 extended by four methylenes), the ligand reaches the point at which significant positional shifts are needed in the binding pocket residues to accommodate the ligand.

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='''Biology of sphingosine 1-phosphate receptors'''=  

           [[Image:Vascular and lymphatic systems new.jpg]]

                 [[Image:Immune system new.jpg]]

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                                     [[Image:Nervous system'.jpg]]