Probing protein flexibility reveals a mechanism for selective promiscuity

Pabon, Nicolas A; Camacho, Carlos J.

doi:10.7554/elife.22889

Cited by 25 publications

(30 citation statements)

References 41 publications

(111 reference statements)

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“…First, MBSs may be more generic and flexible, and in consequence, they may be able to process a broader spectrum of ligands. Examples of this are certain membrane proteins, receptors, and regulatory proteins ( Pabon and Camacho, 2017 ). It has been shown recently that, in the case of a multidrug resistance protein, the conformational variability of its bipartite binding site is the most likely cause of its very broad substrate specificity ( Johnson and Chen, 2017 ).…”

Section: Resultsmentioning

confidence: 99%

Ligand Binding Site Structure Influences the Evolution of Protein Complex Function and Topology

Abrusán

Marsh

2018

Cell Reports

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SummaryIt has been suggested that the evolution of protein complexes is significantly influenced by stochastic, non-adaptive processes. Using ligand binding as a proxy of function, we show that the structure of ligand-binding sites significantly influences the evolution of protein complexes. We show that homomers with multi-chain binding sites (MBSs) evolve new functions slower than monomers or other homomers, and those binding cofactors and metals have more conserved quaternary structure than other homomers. Moreover, the ligands and ligand-binding pockets of homologous MBS homomers are more similar than monomers and other homomers. Our results suggest strong evolutionary selection for quaternary structure in cofactor-binding MBS homomers, whereas neutral processes are more important in complexes with single-chain binding sites. They also have pharmacological implications, suggesting that complexes with single-chain binding sites are better targets for selective drugs, whereas MBS homomers are good candidates for broad-spectrum antibiotic and multitarget drug design.

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Section: Resultsmentioning

confidence: 99%

Ligand Binding Site Structure Influences the Evolution of Protein Complex Function and Topology

Abrusán

Marsh

2018

Cell Reports

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“…However, this study shows that it also limits the ability of the peptide, or in this case the miniprotein, to bind various types of RGD pockets in integrins. The critical proline residues in the RGD-containing loop of 2.5F achieves this fine equilibrium between stability and flexibility enabling focused motional freedom (Krieger et al, 2005;Pabon and Camacho, 2017), where the RGD motif is flexible enough to bind various types of RGD pockets by conformational selection without excessive entropic contribution, which would hamper high affinity binding.…”

Section: Discussionmentioning

confidence: 99%

Structural basis of the differential binding of engineered knottins 2.5F and 2.5D to integrins αVβ3 and α5β1

Agthoven

Shams²,

Cochran

et al. 2019

Preprint

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Integrins αVβ3 and α5β1 play critical roles in tumor survival, invasion, metastasis, and angiogenesis and are validated targets for cancer therapy and molecular imaging. Increasing evidence suggests that targeting both integrins simultaneously with antagonists is more effective in cancer therapy because of concerns about resistance and paradoxical promotion of tumor growth with use of agents highly selective for a single integrin. Engineered Arg-Gly-Asp (RGD)containing 3.5 kDa cysteine-knot proteins (knottins 2.5F and 2.5D) are attractive drug candidates due to their exceptional structural stability and high affinity binding to certain integrins. 2.5F binds both αVβ3 and α5β1, whereas 2.5D is αVβ3-selective. To elucidate the structural basis of integrin selection, we determined the structures of 2.5F and 2.5D both as apo-proteins and in complex with αVβ3. These data, combined with MD simulations and mutational studies, revealed a critical role of two αVβ3-specific residues in the vicinity of the metal ion dependent adhesion site (MIDAS) in promoting an αVβ3-induced fit of 2.5D. In contrast, conformational selection accounted for the specificity of 2.5F to both integrins. These data provide new insights into the structural basis of integrin-ligand binding specificity, and could help in development of integrin-targeted therapeutics.

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“…It is also remarkable the relevance of the residues K 78, D 85, P 89, I 126 and L 128 of the receptor PD-1. These amino-acids have been shown making pairs with almost all pembrolizumab residues, and mutational studies have displayed their relevance to the PD-1/ligand interaction 38 .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the checkpoint protein PD-1 by the therapeutic antibody pembrolizumab outlined by quantum chemistry

Tavares

Neto

Fulco

et al. 2018

Sci Rep

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Much of the recent excitement in the cancer immunotherapy approach has been generated by the recognition that immune checkpoint proteins, like the receptor PD-1, can be blocked by antibody-based drugs with profound effects. Promising clinical data have already been released pointing to the efficiency of the drug pembrolizumab to block the PD-1 pathway, triggering the T-lymphocytes to destroy the cancer cells. Thus, a deep understanding of this drug/receptor complex is essential for the improvement of new drugs targeting the protein PD-1. In this context, by employing quantum chemistry methods based on the Density Functional Theory (DFT), we investigate in silico the binding energy features of the receptor PD-1 in complex with its drug inhibitor. Our computational results give a better understanding of the binding mechanisms, being also an efficient alternative towards the development of antibody-based drugs, pointing to new treatments for cancer therapy.

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Probing protein flexibility reveals a mechanism for selective promiscuity

Cited by 25 publications

References 41 publications

Ligand Binding Site Structure Influences the Evolution of Protein Complex Function and Topology

Ligand Binding Site Structure Influences the Evolution of Protein Complex Function and Topology

Structural basis of the differential binding of engineered knottins 2.5F and 2.5D to integrins αVβ3 and α5β1

Inhibition of the checkpoint protein PD-1 by the therapeutic antibody pembrolizumab outlined by quantum chemistry

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