Binding ofEscherichia coliPrimary Replicative Helicase DnaB Protein to Single-Stranded DNA. Long-Range Allosteric Conformational Changes within the Protein Hexamer†,‡

Biochemistry ◽  
1996 ◽  
Vol 35 (7) ◽  
pp. 2129-2145 ◽  
Author(s):  
Maria J. Jezewska ◽  
Ug-Sung Kim ◽  
Wlodzimierz Bujalowski
Keyword(s):  
Long Range ◽  
Conformational Changes ◽  
Single Stranded Dna ◽  
Replicative Helicase ◽  
Helicase Dnab

scholarly journals FcαRI binding at the IgA1 CH2–CH3 interface induces long-range conformational changes that are transmitted to the hinge region

2018 ◽  
Vol 115 (38) ◽  
pp. E8882-E8891 ◽  
Author(s):  
Monica T. Posgai ◽  
Sam Tonddast-Navaei ◽  
Manori Jayasinghe ◽  
George M. Ibrahim ◽  
George Stan ◽  
...  
Keyword(s):  
Binding Site ◽  
Long Range ◽  
Conformational Changes ◽  
Lectin Binding ◽  
Coarse Grained ◽  
Alanine Scanning Mutagenesis ◽  
Long Distance ◽  
Receptor Binding Site ◽  
Binding Interface ◽  
Functional Dynamics

IgA effector functions include proinflammatory immune responses triggered upon clustering of the IgA-specific receptor, FcαRI, by IgA immune complexes. FcαRI binds to the IgA1–Fc domain (Fcα) at the CH2–CH3 junction and, except for CH2 L257 and L258, all side-chain contacts are contributed by the CH3 domain. In this study, we used experimental and computational approaches to elucidate energetic and conformational aspects of FcαRI binding to IgA. The energetic contribution of each IgA residue in the binding interface was assessed by alanine-scanning mutagenesis and equilibrium surface plasmon resonance (SPR). As expected, hydrophobic residues central to the binding site have strong energetic contributions to the FcαRI:Fcα interaction. Surprisingly, individual mutation of CH2 residues L257 and L258, found at the periphery of the FcαRI binding site, dramatically reduced binding affinity. Comparison of antibody:receptor complexes involving IgA or its precursor IgY revealed a conserved receptor binding site at the CH2–CH3 junction (or its equivalent). Given the importance of residues near the CH2–CH3 junction, we used coarse-grained Langevin dynamics simulations to understand the functional dynamics in Fcα. Our simulations indicate that FcαRI binding, either in an asymmetric (1:1) or symmetric (2:1) complex with Fcα, propagated long-range conformational changes across the Fc domains, potentially impacting the hinge and Fab regions. Subsequent SPR experiments confirmed that FcαRI binding to the Fcα CH2–CH3 junction altered the kinetics of HAA lectin binding at the IgA1 hinge. Receptor-induced long-distance conformational transitions have important implications for the interaction of aberrantly glycosylated IgA1 with anti-glycan autoantibodies in IgA nephropathy.

scholarly journals 3′-Azido-3′-deoxythymidine drug resistance mutations in HIV-1 reverse transcriptase can induce long range conformational changes

1998 ◽  
Vol 95 (16) ◽  
pp. 9518-9523 ◽  
Author(s):  
Jingshan Ren ◽  
Robert M. Esnouf ◽  
Andrew L. Hopkins ◽  
E. Yvonne Jones ◽  
Ian Kirby ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Long Range ◽  
Conformational Changes ◽  
Active Site ◽  
Common Mechanism ◽  
Resistance Mutations ◽  
Hiv Reverse Transcriptase ◽  
Drug Resistance Mutations ◽  
Hiv Rt

HIV reverse transcriptase (RT) is one of the main targets for the action of anti-AIDS drugs. Many of these drugs [e.g., 3′-azido-3′-deoxythymidine (AZT) and 2′,3′-dideoxyinosine (ddI)] are analogues of the nucleoside substrates used by the HIV RT. One of the main problems in anti-HIV therapy is the selection of a mutant virus with reduced drug sensitivity. Drug resistance in HIV is generated for nucleoside analogue inhibitors by mutations in HIV RT. However, most of these mutations are situated some distance from the polymerase active site, giving rise to questions concerning the mechanism of resistance. To understand the possible structural bases for this, the crystal structures of AZT- and ddI-resistant RTs have been determined. For the ddI-resistant RT with a mutation at residue 74, no significant conformational changes were observed for the p66 subunit. In contrast, for the AZT-resistant RT (RTMC) bearing four mutations, two of these (at 215 and 219) give rise to a conformational change that propagates to the active site aspartate residues. Thus, these drug resistance mutations produce an effect at the RT polymerase site mediated simply by the protein. It is likely that such long-range effects could represent a common mechanism for generating drug resistance in other systems.

scholarly journals Designing allostery-inspired response in mechanical networks

2017 ◽  
Vol 114 (10) ◽  
pp. 2520-2525 ◽  
Author(s):  
Jason W. Rocks ◽  
Nidhi Pashine ◽  
Irmgard Bischofberger ◽  
Carl P. Goodrich ◽  
Andrea J. Liu ◽  
...  
Keyword(s):  
Long Range ◽  
Conformational Changes ◽  
Biological Molecules ◽  
Small Subset ◽  
Individual Response ◽  
Computationally Efficient ◽  
Mechanical Responses ◽  
Mechanical Networks ◽  
Disordered Networks ◽  
2D And 3D

Recent advances in designing metamaterials have demonstrated that global mechanical properties of disordered spring networks can be tuned by selectively modifying only a small subset of bonds. Here, using a computationally efficient approach, we extend this idea to tune more general properties of networks. With nearly complete success, we are able to produce a strain between any two target nodes in a network in response to an applied source strain on any other pair of nodes by removing only ∼1% of the bonds. We are also able to control multiple pairs of target nodes, each with a different individual response, from a single source, and to tune multiple independent source/target responses simultaneously into a network. We have fabricated physical networks in macroscopic 2D and 3D systems that exhibit these responses. This work is inspired by the long-range coupled conformational changes that constitute allosteric function in proteins. The fact that allostery is a common means for regulation in biological molecules suggests that it is a relatively easy property to develop through evolution. In analogy, our results show that long-range coupled mechanical responses are similarly easy to achieve in disordered networks.

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