Aromatic Anchor at an Invariant Hormone-Receptor Interface

Pandyarajan, Vijay; Smith, Brian J.; Phillips, Nelson B.; Whittaker, Linda; Cox, Gabriella P.; Wickramasinghe, Nalinda P.; Menting, John G.; Wan, Zi Yi; Whittaker, Jonathan; Ismail‐Beigi, Faramarz; Lawrence, Michael C.; Weiss, Michael A.

doi:10.1074/jbc.m114.608562

Cited by 27 publications

(23 citation statements)

References 86 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These are: initial detachment (opening) of the B-chain C-terminal (BC-CT) of insulin from its hydrophobic (helical) core to expose key binding residues (see Fig 1 A and 1 B ), followed by a rotation and re-modeling of the αCT portion of IR upon the surface of the β-sheet of the L1 domain of IR, and lastly docking of the insulin B-chain α-helix in a parallel orientation to the αCT segment, creating strong hydrophobic interactions in between. Extensive mutagenesis and structural studies of insulin substantiate the critical role of the BC-CT, and in particular the residues F24–Y26, in binding to IR [ 17 , 18 , 21 – 25 ]. Furthermore, the first crystal structure of the insulin–IR complex has revealed the extent of the structural changes and the importance of the BC-CT residues of insulin, especially F24-Y26, as well as the crucial role of H710 and F714 of the αCT segment [ 14 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, all the previous experimental and computational studies on insulin focused on the structural changes that occur in the BC-CT during activation and on mutations in the critical residues, F24 (all the residues mentioned without extra labelling belong to chain B. The A chain residues are denoted by a subscript A) and Y26 [ 15 , 17 – 19 , 21 – 25 , 27 , 28 ]. Two key questions regarding the activation of insulin remain unanswered: the frequency of the BC-CT opening, which is necessary for insulin to bind to the IR, and the mechanism that triggers this opening.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Molecular Dynamics Simulations of Insulin: Elucidating the Conformational Changes that Enable Its Binding

2015

View full text Add to dashboard Cite

A sequence of complex conformational changes is required for insulin to bind to the insulin receptor. Recent experimental evidence points to the B chain C-terminal (BC-CT) as the location of these changes in insulin. Here, we present molecular dynamics simulations of insulin that reveal new insights into the structural changes occurring in the BC-CT. We find three key results: 1) The opening of the BC-CT is inherently stochastic and progresses through an open and then a “wide-open” conformation—the wide-open conformation is essential for receptor binding, but occurs only rarely. 2) The BC-CT opens with a zipper-like mechanism, with a hinge at the Phe24 residue, and is maintained in the dominant closed/inactive state by hydrophobic interactions of the neighboring Tyr26, the critical residue where opening of the BC-CT (activation of insulin) is initiated. 3) The mutation Y26N is a potential candidate as a therapeutic insulin analogue. Overall, our results suggest that the binding of insulin to its receptor is a highly dynamic and stochastic process, where initial docking occurs in an open conformation and full binding is facilitated through interactions of insulin receptor residues with insulin in its wide-open conformation.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulations of Insulin: Elucidating the Conformational Changes that Enable Its Binding

2015

View full text Add to dashboard Cite

show abstract

“…In both mutant insulin Los Angeles and Chicago, aromatic amino residue phenylalanine substituted by non-aromatic serine and leucine respectively leads to changes in binding interaction with IR. The charged or polar side chains reduce the hormone binding (Pandyarajan et al, 2014) and in insulin Los Angeles, the number of polar side chains are increased and this may reduce the binding affinity towards IR.…”

Section: Discussionmentioning

confidence: 99%

Diabetes mellitus caused by mutations in human insulin: analysis of impaired receptor binding of insulinsWakayama,Los AngelesandChicagousing pharmacoinformatics

Islam

Bhayye

Adeniyi

et al. 2016

Journal of Biomolecular Structure and Dynamics

View full text Add to dashboard Cite

Several naturally occuring mutations in the human insulin gene are associated with diabetes mellitus. The three known mutant molecules, Wakayama, Los Angeles and Chicago were evaluated using molecular docking and molecular dynamics (MD) to analyse mechanisms of deprived binding affinity for insulin receptor (IR). Insulin Wakayama, is a variant in which valine at position A3 is substituted by leucine, while in insulin Los Angeles and Chicago, phenylalanine at positions B24 and B25 is replaced by serine and leucine, respectively. These mutations show radical changes in binding affinity for IR. The ZDOCK server was used for molecular docking, while AMBER 14 was used for the MD study. The published crystal structure of IR bound to natural insulin was also used for MD. The binding interactions and MD trajectories clearly explained the critical factors for deprived binding to the IR. The surface area around position A3 was increased when valine was substituted by leucine, while at positions B24 and B25 aromatic amino acid phenylalanine replaced by non-aromatic serine and leucine might be responsible for fewer binding interactions at the binding site of IR that leads to instability of the complex. In the MD simulation, the normal mode analysis, rmsd trajectories and prediction of fluctuation indicated instability of complexes with mutant insulin in order of insulin native insulin< insulin Chicago < insulin Los Angeles < insulin Wakayama molecules which corresponds to the biological evidence of the differing affinities of the mutant insulins for the IR.

show abstract

“…Due to the rapid rise in the number of diabetic people, there is great deal of interest in the development of insulin analogues with enhanced activity and affinity, which can be used for therapeutic purposes. Extensive mutagenesis and structural studies revealed the significant role of the BC-CT—and in particular the triplet of the B-chain aromatic residues F24 B , F25 B and Y26 B —in the activation process of insulin and the binding interface [16] , [22] , [23] , [24] , [25] , [26] , [29] , [30] , [31] , [46] , [47] , [48] , [49] . The F24 B residue has been shown to act as a hinge as the BC-CT opens during the activation of insulin (BC-CT opening) [23] , [25] , [26] , [30] , [46] , while the Y26 B residue has been shown to be a critical residue for the activation of insulin [26] , [30] , [31] , [47] , [48] , [49] .…”

Section: Introductionmentioning

confidence: 99%

“…Although a significant number of experimental studies focus on insulin and its complex structure with the IR [16] , [17] , [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [31] , [32] , [33] , [46] , [47] , [48] , [49] , [50] , as well as on mutations on the critical residues of insulin for predicting potential therapeutic candidates [23] , [25] , [26] , [27] , [31] , [46] , [47] , [48] , [49] , there are still a lot of key features that cannot be solved or are hard to explain using only experimental approaches. There have been relatively few computational studies investigating the conformational changes and dynamics of insulin [25] , [30] , [31] , [51] , [52] , and even less focusing on insulin mutations [25] , [31] , [53] , [54] .…”

Section: Introductionmentioning

confidence: 99%

Computational study of the activity, dynamics, energetics and conformations of insulin analogues using molecular dynamics simulations: Application to hyperinsulinemia and the critical residue B26

Papaioannou

Kuyucak

Kuncic

2017

Biochemistry and Biophysics Reports

View full text Add to dashboard Cite

Due to the increasing prevalence of diabetes, finding therapeutic analogues for insulin has become an urgent issue. While many experimental studies have been performed towards this end, they have limited scope to examine all aspects of the effect of a mutation. Computational studies can help to overcome these limitations, however, relatively few studies that focus on insulin analogues have been performed to date. Here, we present a comprehensive computational study of insulin analogues—three mutant insulins that have been identified with hyperinsulinemia and three mutations on the critical B26 residue that exhibit similar binding affinity to the insulin receptor—using molecular dynamics simulations with the aim of predicting how mutations of insulin affect its activity, dynamics, energetics and conformations. The time evolution of the conformers is studied in long simulations. The probability density function and potential of mean force calculations are performed on each insulin analogue to unravel the effect of mutations on the dynamics and energetics of insulin activation. Our conformational study can decrypt the key features and molecular mechanisms that are responsible for an enhanced or reduced activity of an insulin analogue. We find two key results: 1) hyperinsulinemia may be due to the drastically reduced activity (and binding affinity) of the mutant insulins. 2) Y26BS and Y26BE are promising therapeutic candidates for insulin as they are more active than WT-insulin. The analysis in this work can be readily applied to any set of mutations on insulin to guide development of more effective therapeutic analogues.

show abstract

Aromatic Anchor at an Invariant Hormone-Receptor Interface

Cited by 27 publications

References 86 publications

Molecular Dynamics Simulations of Insulin: Elucidating the Conformational Changes that Enable Its Binding

Molecular Dynamics Simulations of Insulin: Elucidating the Conformational Changes that Enable Its Binding

Diabetes mellitus caused by mutations in human insulin: analysis of impaired receptor binding of insulinsWakayama,Los AngelesandChicagousing pharmacoinformatics

Computational study of the activity, dynamics, energetics and conformations of insulin analogues using molecular dynamics simulations: Application to hyperinsulinemia and the critical residue B26

Contact Info

Product

Resources

About