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Structural identification of the pathway of long-range communication in an allosteric enzyme.

ABSTRACT: Allostery is a common mechanism of regulation of enzyme activity and specificity, and its signatures are readily identified from functional studies. For many allosteric systems, structural evidence exists of long-range communication among protein domains, but rarely has this communication been traced to a detailed pathway. The thrombin mutant D102N is stabilized in a self-inhibited conformation where access to the active site is occluded by a collapse of the entire 215-219 beta-strand. Binding of a fragment of the protease activated receptor PAR1 to exosite I, 30-A away from the active site region, causes a large conformational change that corrects the position of the 215-219 beta-strand and restores access to the active site. The crystal structure of the thrombin-PAR1 complex, solved at 2.2-A resolution, reveals the details of this long-range allosteric communication in terms of a network of polar interactions.

SUBMITTER: Gandhi PS

PROVIDER: S-EPMC2538848 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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Structural identification of the pathway of long-range communication in an allosteric enzyme.

Gandhi Prafull S PS Chen Zhiwei Z Mathews F Scott FS Di Cera Enrico E

Proceedings of the National Academy of Sciences of the United States of America 20080204 6

Allostery is a common mechanism of regulation of enzyme activity and specificity, and its signatures are readily identified from functional studies. For many allosteric systems, structural evidence exists of long-range communication among protein domains, but rarely has this communication been traced to a detailed pathway. The thrombin mutant D102N is stabilized in a self-inhibited conformation where access to the active site is occluded by a collapse of the entire 215-219 beta-strand. Binding o ...[more]

PMID: 18250335

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Project description:The phenomenon of intra-protein communication is fundamental to such processes as allostery and signaling, yet comparatively little is understood about its physical origins despite notable progress in recent years. This review introduces contemporary but distinct frameworks for understanding intra-protein communication by presenting both the ideas behind them and a discussion of their successes and shortcomings. The first framework holds that intra-protein communication is accomplished by the sequential mechanical linkage of residues spanning a gap between distal sites. According to the second framework, proteins are best viewed as ensembles of distinct structural microstates, the dynamical and thermodynamic properties of which contribute to the experimentally observable macroscale properties. Nuclear magnetic resonance (NMR) spectroscopy is a powerful method for studying intra-protein communication, and the insights into both frameworks it provides are presented through a discussion of numerous examples from the literature. Distinct from mechanical and thermodynamic considerations of intra-protein communication are recently applied graph and network theoretic analyses. These computational methods reduce complex three dimensional protein architectures to simple maps comprised of nodes (residues) connected by edges (inter-residue "interactions"). Analysis of these graphs yields a characterization of the protein's topology and network characteristics. These methods have shown proteins to be "small world" networks with moderately high local residue connectivities existing concurrently with a small but significant number of long range connectivities. However, experimental studies of the tantalizing idea that these putative long range interaction pathways facilitate one or several macroscopic protein characteristics are unfortunately lacking at present. This review concludes by comparing and contrasting the presented frameworks and methodologies for studying intra-protein communication and suggests a manner in which they can be brought to bear simultaneously to further enhance our understanding of this important fundamental phenomenon.

Project description:Severe acute respiratory syndrome (SARS) and novel coronavirus disease (COVID-19) are caused by two closely related beta-coronaviruses, SARS-CoV and SARS-CoV-2, respectively. The envelopes surrounding these viruses are decorated with spike proteins, whose receptor binding domains (RBDs) initiate invasion by binding to the human angiotensin-converting enzyme 2 (ACE2). Subtle changes at the interface with ACE2 seem to be responsible for the enhanced affinity for the receptor of the SARS-CoV-2 RBD compared to SARS-CoV RBD. Here, we use Elastic Network Models (ENMs) to study the response of the viral RBDs and ACE2 upon dissassembly of the complexes. We identify a dominant detachment mode, in which the RBD rotates away from the surface of ACE2, while the receptor undergoes a conformational transition which stretches the active-site cleft. Using the Structural Perturbation Method, we determine the network of residues, referred to as the Allostery Wiring Diagram (AWD), which drives the large-scale motion activated by the detachment of the complex. The AWD for SARS-CoV and SARS-CoV-2 are remarkably similar, showing a network that spans the interface of the complex and reaches the active site of ACE2, thus establishing an allosteric connection between RBD binding and receptor catalytic function. Informed in part by the AWD, we used Molecular Dynamics simulations to probe the effect of interfacial mutations in which SARS-CoV-2 residues are replaced by their SARS-CoV counterparts. We focused on a conserved glycine (G502 in SARS-CoV-2, G488 in SARS-CoV) because it belongs to a region that initiates the dissociation of the complex along the dominant detachment mode, and is prominent in the AWD. Molecular Dynamics simulations of SARS-CoV-2 wild-type and G502P mutant show that the affinity for the human receptor of the mutant is drastically diminished. Our results suggest that in addition to residues that are in direct contact with the interface those involved in long range allosteric communication are also a determinant of the stability of the RBD-ACE2 complex.

Dataset Information

Structural identification of the pathway of long-range communication in an allosteric enzyme.

Publications

Structural identification of the pathway of long-range communication in an allosteric enzyme.

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