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The importance of N-glycosylation on ?3 integrin ligand binding and conformational regulation.

ABSTRACT: N-glycosylations can regulate the adhesive function of integrins. Great variations in both the number and distribution of N-glycosylation sites are found in the 18 ? and 8 ? integrin subunits. Crystal structures of ?IIb?3 and ?V?3 have resolved the precise structural location of each N-glycan site, but the structural consequences of individual N-glycan site on integrin activation remain unclear. By site-directed mutagenesis and structure-guided analyses, we dissected the function of individual N-glycan sites in ?3 integrin activation. We found that the N-glycan site, ?3-N320 at the headpiece and leg domain interface positively regulates ?IIb?3 but not ?V?3 activation. The ?3-N559 N-glycan at the ?3-I-EGF3 and ?IIb-calf-1 domain interface, and the ?3-N654 N-glycan at the ?3-?-tail and ?IIb-calf-2 domain interface positively regulate the activation of both ?IIb?3 and ?V?3 integrins. In contrast, removal of the ?3-N371 N-glycan near the ?3 hybrid and I-EGF3 interface, or the ?3-N452 N-glycan at the I-EGF1 domain rendered ?3 integrin more active than the wild type. We identified one unique N-glycan at the ?I domain of ?1 subunit that negatively regulates ?5?1 activation. Our study suggests that the bulky N-glycans influence the large-scale conformational rearrangement by potentially stabilizing or destabilizing the domain interfaces of integrin.

SUBMITTER: Cai X

PROVIDER: S-EPMC5498496 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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The importance of N-glycosylation on β3 integrin ligand binding and conformational regulation.

Cai Xiulei X Thinn Aye Myat Myat AMM Wang Zhengli Z Shan Hu H Zhu Jieqing J

Scientific reports 20170705 1

N-glycosylations can regulate the adhesive function of integrins. Great variations in both the number and distribution of N-glycosylation sites are found in the 18 α and 8 β integrin subunits. Crystal structures of αIIbβ3 and αVβ3 have resolved the precise structural location of each N-glycan site, but the structural consequences of individual N-glycan site on integrin activation remain unclear. By site-directed mutagenesis and structure-guided analyse ...[more]

PMID: 28680094

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Project description:Accurate prediction of the binding affinities of small-molecule ligands to their biological targets is fundamental for structure-based drug design but remains a very challenging task. In this paper, we have performed computational studies to predict the binding models of 31 small-molecule Smac (the second mitochondria-derived activator of caspase) mimetics to their target, the XIAP (X-linked inhibitor of apoptosis) protein, and their binding affinities. Our results showed that computational docking was able to reliably predict the binding models, as confirmed by experimentally determined crystal structures of some Smac mimetics complexed with XIAP. However, all the computational methods we have tested, including an empirical scoring function, two knowledge-based scoring functions, and MM-GBSA (molecular mechanics and generalized Born surface area), yield poor to modest prediction for binding affinities. The linear correlation coefficient (r(2)) value between the predicted affinities and the experimentally determined affinities was found to be between 0.21 and 0.36. Inclusion of ensemble protein-ligand conformations obtained from molecular dynamic simulations did not significantly improve the prediction. However, major improvement was achieved when the free-energy change for ligands between their free- and bound-states, or "ligand-reorganization free energy", was included in the MM-GBSA calculation, and the r(2) value increased from 0.36 to 0.66. The prediction was validated using 10 additional Smac mimetics designed and evaluated by an independent group. This study demonstrates that ligand reorganization free energy plays an important role in the overall binding free energy between Smac mimetics and XIAP. This term should be evaluated for other ligand-protein systems and included in the development of new scoring functions. To our best knowledge, this is the first computational study to demonstrate the importance of ligand reorganization free energy for the prediction of protein-ligand binding free energy.

Dataset Information

The importance of N-glycosylation on ?3 integrin ligand binding and conformational regulation.

Publications

The importance of N-glycosylation on β<sub>3</sub> integrin ligand binding and conformational regulation.

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