Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

A minimal ligand binding pocket within a network of correlated mutations identified by multiple sequence and structural analysis of G protein coupled receptors.

Moitra, Subhodeep and Tirupula, Kalyan C and Klein-Seetharaman, Judith and Langmead, Christopher James (2012) A minimal ligand binding pocket within a network of correlated mutations identified by multiple sequence and structural analysis of G protein coupled receptors. BMC Biophys, 5. 13 - ?.

[img]
Preview
PDF
Published Version
Available under License : See the attached license file.

Download (1MB) | Preview
[img] Plain Text (licence)
Available under License : See the attached license file.

Download (1kB)

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.


Share

Citation/Export:
Social Networking:
Share |

Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Moitra, Subhodeep
Tirupula, Kalyan C
Klein-Seetharaman, Judith
Langmead, Christopher James
Date: 21 June 2012
Date Type: Acceptance
Journal or Publication Title: BMC Biophys
Volume: 5
Page Range: 13 - ?
DOI or Unique Handle: 10.1186/2046-1682-5-13
Schools and Programs: School of Medicine > Structural Biology
Refereed: Yes
Date Deposited: 29 Nov 2016 21:01
Last Modified: 14 Oct 2017 05:58
URI: http://d-scholarship.pitt.edu/id/eprint/29869

Metrics

Monthly Views for the past 3 years

Plum Analytics

Altmetric.com


Actions (login required)

View Item View Item