Progress towards the development of SH2 domain inhibitors

Kraskouskaya, Dziyana; Duodu, Eugenia; Arpin, Carolynn C.; Gunning, Patrick T.

doi:10.1039/c3cs35449k

Cited by 103 publications

(82 citation statements)

References 306 publications

(363 reference statements)

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“…Since many SH2 domain proteins are implicated in human diseases, SH2 domains have been targeted for drug development (Kraskouskaya et al, 2013); however, extensive efforts to modulate their pY binding have met with limited success, due to structural similarity and ligand promiscuity of the pY-binding pockets. Our study showing the ligand specificity and structural diversity of lipid binding sites of SH2 domains, in conjunction with the finding that many disease-causing mutations of SH2 domain proteins are found in the lipid-binding sites of SH2 domains (Table 2), could point a way toward a new alternate strategy for controlling pY signaling activities with improved specificity and potency.…”

Section: Discussionmentioning

confidence: 99%

SH2 Domains Serve as Lipid-Binding Modules for pTyr-Signaling Proteins

et al. 2016

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SUMMARY The Src-homology 2 (SH2) domain is a protein interaction domain that directs myriad phosphotyrosine (pY) signaling pathways. Genome-wide screening of human SH2 domains reveals that ≈90% of SH2 domains bind plasma membrane lipids and many have high phosphoinositide specificity. They bind lipids using surface cationic patches separate from pY-binding pockets, thus binding lipids and the pY motif independently. The patches form grooves for specific lipid headgroup recognition or flat surfaces for non-specific membrane binding and both types of interaction is important for cellular function and regulation of SH2 domain-containing proteins. Cellular studies with ZAP70 showed that multiple lipids bind its C-terminal SH2 domain in a spatiotemporally specific manner and thereby exert exquisite spatiotemporal control over its protein binding and signaling activities in T cells. Collectively, these studies reveal how lipids control SH2 domain-mediated cellular protein-protein interaction networks and suggest a new strategy for therapeutic modulation of pY signaling pathways.

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Section: Discussionmentioning

confidence: 99%

SH2 Domains Serve as Lipid-Binding Modules for pTyr-Signaling Proteins

et al. 2016

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“…In addition, we also should consider the possibility of formation of a CD28 dimer in which multivalent binding would increase the affinity relative to monovalent binding due to the effect of avidity (27). Nevertheless, the interaction of SH2 itself mainly contributes to CD28 binding, and therefore the high resolution structure information presented here will help to generate compounds to selectively inhibit the respective CD28 interactions (28). Such compounds would specifically modulate CD28 co-stimulatory signaling without affecting the function of other co-stimulatory molecules, such as inducible co-stimulator, CTLA-4, and PD-1 (29 -31).…”

Section: Discussionmentioning

confidence: 99%

Crystal Structures and Thermodynamic Analysis Reveal Distinct Mechanisms of CD28 Phosphopeptide Binding to the Src Homology 2 (SH2) Domains of Three Adaptor Proteins

Inaba

Numoto

Ogawa

et al. 2017

Journal of Biological Chemistry

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Edited by Norma AllewellFull activation of T cells and differentiation into effector T cells are essential for many immune responses and require costimulatory signaling via the CD28 receptor. Extracellular ligand binding to CD28 recruits protein-tyrosine kinases to its cytoplasmic tail, which contains a YMNM motif. Following phosphorylation of the tyrosine, the proteins growth factor receptorbound protein 2 (Grb2), Grb2-related adaptor downstream of Shc (Gads), and p85 subunit of phosphoinositide 3-kinase may bind to pYMNM (where pY is phosphotyrosine) via their Src homology 2 (SH2) domains, leading to downstream signaling to distinct immune pathways. These three adaptor proteins bind to the same site on CD28 with variable affinity, and all are important for CD28-mediated co-stimulatory function. However, the mechanism of how these proteins recognize and compete for CD28 is unclear. To visualize their interactions with CD28, we have determined the crystal structures of Gads SH2 and two p85 SH2 domains in complex with a CD28-derived phosphopeptide. The high resolution structures obtained revealed that, whereas the CD28 phosphopeptide bound to Gads SH2 is in a bent conformation similar to that when bound to Grb2 SH2, it adopts a more extended conformation when bound to the N-and C-terminal SH2 domains of p85. These differences observed in the peptide-protein interactions correlated well with the affinity and other thermodynamic parameters for each interaction determined by isothermal titration calorimetry. The detailed insight into these interactions reported here may inform the development of compounds that specifically inhibit the association of CD28 with these adaptor proteins to suppress excessive T cell responses, such as in allergies and autoimmune diseases.

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“…PI3 kinases are correlated with various diseases such as cancer [10]. Taking this aspect into account, it is not surprising that addressing the SH2 binding domain is an important strategy for therapeutic purposes [11]. A mixed kinase affinity resin for the evaluation of ATP competitive kinase inhibitors, called Kinobeads [12] is available and a comparable affinity-based approach for the evaluation of SH2 addressing inhibitors would be desirable.…”

Section: Introductionmentioning

confidence: 99%

Probing SH2-domains using Inhibitor Affinity Purification (IAP)

et al. 2014

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BackgroundMany human diseases are correlated with the dysregulation of signal transduction processes. One of the most important protein interaction domains in the context of signal transduction is the Src homology 2 (SH2) domain that binds phosphotyrosine residues. Hence, appropriate methods for the investigation of SH2 proteins are indispensable in diagnostics and medicinal chemistry. Therefore, an affinity resin for the enrichment of all SH2 proteins in one experiment would be desirable. However, current methods are unable to address all SH2 proteins simultaneously with a single compound or a small array of compounds.ResultsIn order to overcome these limitations for the investigation of this particular protein family in future experiments, a dipeptide-derived probe has been designed, synthesized and evaluated. This probe successfully enriched 22 SH2 proteins from mixed cell lysates which contained 50 SH2 proteins. Further characterization of the SH2 binding properties of the probe using depletion and competition experiments indicated its ability to enrich complexes consisting of SH2 domain bearing regulatory PI3K subunits and catalytic phosphoinositide 3-kinase (PI3K) subunits that have no SH2 domain.ConclusionThe results make this probe a promising starting point for the development of a mixed affinity resin with complete SH2 protein coverage. Moreover, the additional findings render it a valuable tool for the evaluation of PI3K complex interrupting inhibitors.

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Progress towards the development of SH2 domain inhibitors

Cited by 103 publications

References 306 publications

SH2 Domains Serve as Lipid-Binding Modules for pTyr-Signaling Proteins

SH2 Domains Serve as Lipid-Binding Modules for pTyr-Signaling Proteins

Crystal Structures and Thermodynamic Analysis Reveal Distinct Mechanisms of CD28 Phosphopeptide Binding to the Src Homology 2 (SH2) Domains of Three Adaptor Proteins

Probing SH2-domains using Inhibitor Affinity Purification (IAP)

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