The Mechanism of Allosteric Inhibition of Protein Tyrosine Phosphatase 1B

Abstract

As the prototypical member of the PTP family, protein tyrosine phosphatase 1B (PTP1B) is an attractive target for therapeutic interventions in type 2 diabetes. The extremely conserved catalytic site of PTP1B renders the design of selective PTP1B inhibitors intractable. Although discovered allosteric inhibitors containing a benzofuran sulfonamide scaffold offer fascinating opportunities to overcome selectivity issues, the allosteric inhibitory mechanism of PTP1B has remained elusive. Here, molecular dynamics (MD) simulations, coupled with a dynamic weighted community analysis, were performed to unveil the potential allosteric signal propagation pathway from the allosteric site to the catalytic site in PTP1B. This result revealed that the allosteric inhibitor compound-3 induces a conformational rearrangement in helix α7, disrupting the triangular interaction among helix α7, helix α3, and loop11. Helix α7 then produces a force, pulling helix α3 outward, and promotes Ser190 to interact with Tyr176. As a result, the deviation of Tyr176 abrogates the hydrophobic interactions with Trp179 and leads to the downward movement of the WPD loop, which forms an H-bond between Asp181 and Glu115. The formation of this H-bond constrains the WPD loop to its open conformation and thus inactivates PTP1B. The discovery of this allosteric mechanism provides an overall view of the regulation of PTP1B, which is an important insight for the design of potent allosteric PTP1B inhibitors.

Conformational Rigidity and Protein Dynamics at Distinct Timescales Regulate PTP1B Activity and Allostery

“…When benzofuran compounds bind this pocket, the activity of PTP1B is potently inhibited. Although initial molecular dynamics (MD) studies suggested that truncating and/or mutating helix α7 affects WPD loop closure (Li et al, 2014; Olmez and Alakent, 2011; Shinde and Sobhia, 2013), there is still no molecular model that explains how perturbations from the allosteric site are propagated to the active site. Furthermore, the role of dynamics and/or conformational changes in this process remain essential, open questions.…”

Eigenvector centrality for characterization of protein allosteric pathways

“…Thus, establishing a molecular level understanding of communication pathways between the physically distant enzymatic sites is crucial for the design of innovative drug therapies[1, 2] and protein engineering [3][4][5].Recently, there have been significant efforts toward the development of computational tools to support, interpret and/or predict experimental evidences for elucidation of allosteric pathways in proteins [2,[6][7][8][9][10][11][12]. Network analysis has been extensively used in this context, by incorporating concepts and methodologies from graph theory into the realm of molecular dynamics simulations [13][14][15][16][17][18][19] For instance, community network analysis (CNA) has emerged as a powerful and increasingly popular approach to analyze the dynamics of enzymes and protein/DNA (and/or RNA) complexes and to detect possible allosteric pathways [20][21][22][23][24][25][26].In these network theory-based approaches, a protein is represented as a network consisting of a set of nodes, n connected by edges, m. Usually, each amino acid is associated to a node (typically positioned on the alpha carbon or the center of mass of the residue side chain). Depending on the physical property of interest, there are multiple quantities that can characterize the edges (i.e.…”

Novel Non-carboxylate Benzoylsulfonamide-Based Protein Tyrosine Phosphatase 1B Inhibitors with Non-competitive Actions

“…Several X-ray crystal structure analyses and computational simulations recently revealed the binding sites of allosteric inhibitors and the inhibitory mechanisms in which a small molecule binds to allosteric sites and stabilizes the conformation associated with the inactive state of PTP1B. [37][38][39][40][41][42][43][44] Based on the molecular similarities between our compound 18K and an allosteric inhibitor bound to PTP1B (Fig. 2a), we constructed a structural model of the 18K-PTP1B complex by molecular alignment of the compounds, followed by validation and refinement of the structure obtained using a molecular dynamic (MD) simulation.…”