TY - JOUR
T1 - Structure and computation-guided yeast surface display for the evolution of TIMP-based matrix metalloproteinase inhibitors
AU - Shoari, Alireza
AU - Khalili-Tanha, Ghazaleh
AU - Coban, Mathew A.
AU - Radisky, Evette S.
N1 - Publisher Copyright:
Copyright © 2023 Shoari, Khalili-Tanha, Coban and Radisky.
PY - 2023
Y1 - 2023
N2 - The study of protein-protein interactions (PPIs) and the engineering of protein-based inhibitors often employ two distinct strategies. One approach leverages the power of combinatorial libraries, displaying large ensembles of mutant proteins, for example, on the yeast cell surface, to select binders. Another approach harnesses computational modeling, sifting through an astronomically large number of protein sequences and attempting to predict the impact of mutations on PPI binding energy. Individually, each approach has inherent limitations, but when combined, they generate superior outcomes across diverse protein engineering endeavors. This synergistic integration of approaches aids in identifying novel binders and inhibitors, fine-tuning specificity and affinity for known binding partners, and detailed mapping of binding epitopes. It can also provide insight into the specificity profiles of varied PPIs. Here, we outline strategies for directing the evolution of tissue inhibitors of metalloproteinases (TIMPs), which act as natural inhibitors of matrix metalloproteinases (MMPs). We highlight examples wherein design of combinatorial TIMP libraries using structural and computational insights and screening these libraries of variants using yeast surface display (YSD), has successfully optimized for MMP binding and selectivity, and conferred insight into the PPIs involved.
AB - The study of protein-protein interactions (PPIs) and the engineering of protein-based inhibitors often employ two distinct strategies. One approach leverages the power of combinatorial libraries, displaying large ensembles of mutant proteins, for example, on the yeast cell surface, to select binders. Another approach harnesses computational modeling, sifting through an astronomically large number of protein sequences and attempting to predict the impact of mutations on PPI binding energy. Individually, each approach has inherent limitations, but when combined, they generate superior outcomes across diverse protein engineering endeavors. This synergistic integration of approaches aids in identifying novel binders and inhibitors, fine-tuning specificity and affinity for known binding partners, and detailed mapping of binding epitopes. It can also provide insight into the specificity profiles of varied PPIs. Here, we outline strategies for directing the evolution of tissue inhibitors of metalloproteinases (TIMPs), which act as natural inhibitors of matrix metalloproteinases (MMPs). We highlight examples wherein design of combinatorial TIMP libraries using structural and computational insights and screening these libraries of variants using yeast surface display (YSD), has successfully optimized for MMP binding and selectivity, and conferred insight into the PPIs involved.
KW - directed evolution
KW - matrix metalloproteinase
KW - protein engineering
KW - tissue inhibitor of metalloproteinases
KW - yeast surface display
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U2 - 10.3389/fmolb.2023.1321956
DO - 10.3389/fmolb.2023.1321956
M3 - Short survey
AN - SCOPUS:85178935830
SN - 2296-889X
VL - 10
JO - Frontiers in Molecular Biosciences
JF - Frontiers in Molecular Biosciences
M1 - 1321956
ER -