title: A minimal ligand binding pocket within a network of correlated mutations identified by multiple sequence and structural analysis of G protein coupled receptors.
abstract: BACKGROUND
  G protein coupled receptors (GPCRs) are seven helical transmembrane proteins that function as signal transducers. They bind ligands in their extracellular and transmembrane regions and activate cognate G proteins at their intracellular surface at the other side of the membrane. The relay of allosteric communication between the ligand binding site and the distant G protein binding site is poorly understood. In this study, GREMLIN        1, a recently developed method that identifies networks of co-evolving residues from multiple sequence alignments, was used to identify those that may be involved in communicating the activation signal across the membrane. The GREMLIN-predicted long-range interactions between amino acids were analyzed with respect to the seven GPCR structures that have been crystallized at the time this study was undertaken.
  
  
  RESULTS
  GREMLIN significantly enriches the edges containing residues that are part of the ligand binding pocket, when compared to a control distribution of edges drawn from a random graph. An analysis of these edges reveals a minimal GPCR binding pocket containing four residues (T1183.33, M2075.42, Y2686.51 and A2927.39). Additionally, of the ten residues predicted to have the most long-range interactions (A1173.32, A2726.55, E1133.28, H2115.46, S186EC2, A2927.39, E1223.37, G902.57, G1143.29 and M2075.42), nine are part of the ligand binding pocket.
  
  
  CONCLUSIONS
  We demonstrate the use of GREMLIN to reveal a network of statistically correlated and functionally important residues in class A GPCRs. GREMLIN identified that ligand binding pocket residues are extensively correlated with distal residues. An analysis of the GREMLIN edges across multiple structures suggests that there may be a minimal binding pocket common to the seven known GPCRs. Further, the activation of rhodopsin involves these long-range interactions between extracellular and intracellular domain residues mediated by the retinal domain.
authors: Computer Science Department, Carnegie Mellon University, Gates Hillman Center, 5000 Forbes Avenue, Pittsburgh, PA, USA.
authors: Subhodeep
authors: S
authors: Moitra
authors: Department of Structural Biology, University of Pittsburgh School of Medicine, Rm. 2051, Biomedical Science Tower 3, 3501 Fifth Avenue, Pittsburgh, PA, USA.
authors: Kalyan C
authors: KC
authors: Tirupula
authors: Department of Structural Biology, University of Pittsburgh School of Medicine, Rm. 2051, Biomedical Science Tower 3, 3501 Fifth Avenue, Pittsburgh, PA, USA.
authors: Judith
authors: J
authors: Klein-Seetharaman
authors: Computer Science Department, Carnegie Mellon University, Gates Hillman Center, 5000 Forbes Avenue, Pittsburgh, PA, USA.
authors: Christopher James
authors: CJ
authors: Langmead