Cavity architecture based modulation of ligand binding tunnels in plant START domains

Mahtha, Sanjeet Kumar; Kumari, Kamlesh; Gaur, Vineet; Yadav, Gitanjali

doi:10.1016/j.csbj.2023.07.039

Cited by 2 publications

(2 citation statements)

References 57 publications

(78 reference statements)

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“…For example, the immunoglobulin fold used by antibodies is quite successful in the molecular recognition of both protein and small molecule ligands 23,24 . Members of both the lipocalin fold and the START superfamily naturally bind, and can further be engineered to bind, a variety of small molecule ligands [25][26][27][28][29][30] . Richer information on the sequence, structural, and mechanistic basis of ligand binding may be found by interrogating a sensor family's recognition of distinct ligands rather than bespoke designs.…”

Section: Introductionmentioning

confidence: 99%

Rationalizing diverse binding mechanisms to the same protein fold: insights for ligand recognition and biosensor design

Leonard,

Friedman,

Chayer

et al. 2024

Preprint

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The engineering of novel protein-ligand binding interactions, particularly for complex drug-like molecules, is an unsolved problem which could enable many practical applications of protein biosensors. In this work, we analyzed two engineered biosensors, derived from the plant hormone sensor PYR1, to recognize either the agrochemical mandipropamid or the syn-thetic cannabinoid WIN55,212-2. Using a combination of quantitative deep mutational scanning experiments and molecular dynamics simulations, we demonstrated that mutations at common positions can promote protein-ligand shape complemen-tarity and revealed prominent differences in the electrostatic networks needed to complement diverse ligands. MD simula-tions indicate that both PYR1 protein-ligand complexes bind a single conformer of their target ligand that is close to the lowest free energy conformer. Computational design using a fixed conformer and rigid body orientation led to new WIN55,212-2 sensors with nanomolar limits of detection. This work reveals mechanisms by which the versatile PYR1 bio-sensor scaffold can bind diverse ligands. This work also provides computational methods to sample realistic ligand conform-ers and rigid body alignments that simplify the computational design of biosensors for novel ligands of interest.

show abstract

Section: Introductionmentioning

confidence: 99%

Rationalizing diverse binding mechanisms to the same protein fold: insights for ligand recognition and biosensor design

Leonard,

Friedman,

Chayer

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…However, several protein folds have evolved and been engineered to bind diverse ligands with affinity and specificity. For example, the immunoglobulin fold used by antibodies is quite successful in the molecular recognition of both protein and small molecule ligands. , Members of both the lipocalin fold and the START superfamily naturally bind, and can further be engineered to bind, a variety of small molecule ligands. − Richer information on the sequence, structural, and mechanistic basis of ligand binding may be found by interrogating a sensor family’s recognition of distinct ligands rather than bespoke designs.…”

Section: Introductionmentioning

confidence: 99%

Rationalizing Diverse Binding Mechanisms to the Same Protein Fold: Insights for Ligand Recognition and Biosensor Design

Leonard,

Friedman,

Chayer

et al. 2024

ACS Chem. Biol.

View full text Add to dashboard Cite

The engineering of novel protein−ligand binding interactions, particularly for complex drug-like molecules, is an unsolved problem, which could enable many practical applications of protein biosensors. In this work, we analyzed two engineered biosensors, derived from the plant hormone sensor PYR1, to recognize either the agrochemical mandipropamid or the synthetic cannabinoid WIN55,212-2. Using a combination of quantitative deep mutational scanning experiments and molecular dynamics simulations, we demonstrated that mutations at common positions can promote protein−ligand shape complementarity and revealed prominent differences in the electrostatic networks needed to complement diverse ligands. MD simulations indicate that both PYR1 protein−ligand complexes bind a single conformer of their target ligand that is close to the lowest free-energy conformer. Computational design using a fixed conformer and rigid body orientation led to new WIN55,212-2 sensors with nanomolar limits of detection. This work reveals mechanisms by which the versatile PYR1 biosensor scaffold can bind diverse ligands. This work also provides computational methods to sample realistic ligand conformers and rigid body alignments that simplify the computational design of biosensors for novel ligands of interest.

show abstract

Cavity architecture based modulation of ligand binding tunnels in plant START domains

Cited by 2 publications

References 57 publications

Rationalizing diverse binding mechanisms to the same protein fold: insights for ligand recognition and biosensor design

Rationalizing diverse binding mechanisms to the same protein fold: insights for ligand recognition and biosensor design

Rationalizing Diverse Binding Mechanisms to the Same Protein Fold: Insights for Ligand Recognition and Biosensor Design

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