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Anionic block copolymerization of styrene and divinylbenzene is known to lead to the formation of star-shaped macromolecules. This “arm-first” method has been widely used and studied. The present paper is devoted to two special aspects of this method: The first is concerned with the efficiency of the protection exerted by the arms on the crosslinked core, preventing gelation of the reaction medium. A number of “porcupine” polymers involving bulky cores, fitted with a large number of arms, were synthesized and characterized. The second deals with the possibility of using the “living” carbanionic sites present in the cores, either for purpose of functionalization, or to grow new branches from the core. The presence of remaining unsaturations in the core was evidenced. This is a drawback, since the possibility for “transverse” bonds to be formed results in couplings, inducing gelation. 相似文献
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John G. Menting Yanwu Yang Shu Jin Chan Nelson B. Phillips Brian J. Smith Jonathan Whittaker Nalinda P. Wickramasinghe Linda J. Whittaker Vijay Pandyarajan Zhu-li Wan Satya P. Yadav Julie M. Carroll Natalie Strokes Charles T. Roberts Jr. Faramarz Ismail-Beigi Wieslawa Milewski Donald F. Steiner Virander S. Chauhan Colin W. Ward Michael A. Weiss Michael C. Lawrence 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(33):E3395-E3404
Insulin provides a classical model of a globular protein, yet how the hormone changes conformation to engage its receptor has long been enigmatic. Interest has focused on the C-terminal B-chain segment, critical for protective self-assembly in β cells and receptor binding at target tissues. Insight may be obtained from truncated “microreceptors” that reconstitute the primary hormone-binding site (α-subunit domains L1 and αCT). We demonstrate that, on microreceptor binding, this segment undergoes concerted hinge-like rotation at its B20-B23 β-turn, coupling reorientation of PheB24 to a 60° rotation of the B25-B28 β-strand away from the hormone core to lie antiparallel to the receptor''s L1–β2 sheet. Opening of this hinge enables conserved nonpolar side chains (IleA2, ValA3, ValB12, PheB24, and PheB25) to engage the receptor. Restraining the hinge by nonstandard mutagenesis preserves native folding but blocks receptor binding, whereas its engineered opening maintains activity at the price of protein instability and nonnative aggregation. Our findings rationalize properties of clinical mutations in the insulin family and provide a previously unidentified foundation for designing therapeutic analogs. We envisage that a switch between free and receptor-bound conformations of insulin evolved as a solution to conflicting structural determinants of biosynthesis and function.How insulin engages the insulin receptor has inspired speculation ever since the structure of the free hormone was determined by Hodgkin and colleagues in 1969 (1, 2). Over the ensuing decades, anomalies encountered in studies of analogs have suggested that the hormone undergoes a conformational change on receptor binding: in particular, that the C-terminal β-strand of the B chain (residues B24–B30) releases from the helical core to expose otherwise-buried nonpolar surfaces (the detachment model) (3–6). Interest in the B-chain β-strand was further motivated by the discovery of clinical mutations within it associated with diabetes mellitus (DM) (7). Analysis of residue-specific photo–cross-linking provided evidence that both the detached strand and underlying nonpolar surfaces engage the receptor (8).The relevant structural biology is as follows. The insulin receptor is a disulfide-linked (αβ)2 receptor tyrosine kinase (Fig. 1A), the extracellular α-subunits together binding a single insulin molecule with high affinity (9). Involvement of the two α-subunits is asymmetric: the primary insulin-binding site (site 1*) comprises the central β-sheet (L1–β2) of the first leucine-rich repeat domain (L1) of one α-subunit and the partially helical C-terminal segment (αCT) of the other α-subunit (Fig. 1A) (10). Such binding initiates conformational changes leading to transphosphorylation of the β-subunits’ intracellular tyrosine kinase (TK) domains. Structures of wild-type (WT) insulin (or analogs) bound to extracellular receptor fragments were recently described at maximum resolution of 3.9 Å (11), revealing that hormone binding is primarily mediated by αCT (receptor residues 704–719); direct interactions between insulin and L1 were sparse and restricted to certain B-chain residues. On insulin binding, αCT was repositioned on the L1–β2 surface, and its helix was C-terminally extended to include residues 711–714. None of these structures defined the positions of C-terminal B-chain residues beyond B21. Support for the detachment model was nonetheless provided by entry of αCT into a volume that would otherwise be occupied by B-chain residues B25–B30 (i.e., in classical insulin structures; Fig. 1B) (11).Open in a separate windowFig. 1.Insulin B-chain C-terminal β-strand in the μIR complex. (A) Structure of apo-receptor ectodomain. One monomer is in tube representation (labeled), the second is in surface representation. L1, first leucine-rich repeat domain; CR, cysteine-rich domain; L2, second leucine-rich repeat domain; FnIII-1, -2 and -3; first, second and third fibronectin type III domains, respectively; αCT, α-subunit C-terminal segment; coral disk, plasma membrane. (B) Insulin bound to μIR; the view direction with respect to L1 in the apo-ectodomain is indicated by the arrow in A. Only B-chain residues indicated in black were originally resolved (11). The brown tube indicates classical location of residues B20-B30 in free insulin, occluded in the complex by αCT. (C) Orthogonal views of unmodeled 2Fobs-Fcalc difference electron density (SI Appendix), indicating association of map segments with the αCT C-terminal extension (transparent magenta), insulin B-chain C-terminal segment (transparent gray), and AsnA21 (transparent yellow). Difference density is sharpened (Bsharp = −160 Å2). (D–F) Refined models of respective segments insulin B20–B27, αCT 714–719, and insulin A17-A21 within postrefinement 2Fobs-Fcalc difference electron density (Bsharp = −160 Å2). D is in stereo.We describe here the structure and interactions of the detached B-chain C-terminal segment of insulin on its binding to a “microreceptor” (μIR), an L1–CR domain-minimized version of the α-subunit (designated IR310.T) plus exogenous αCT peptide 704–719 (11). Our analysis defines a hinge in the B chain whose opening is coupled to repositioning of αCT between nonpolar surfaces of L1 and the insulin A chain. To understand the role of this hinge in holoreceptor binding and signaling, we designed three insulin analogs containing structural constraints (d-AlaB20, d-AlaB23]-insulin, ∆PheB25-insulin, and ∆PheB24-insulin, where ∆Phe is (α,β)-dehydrophenylalanine (Fig. 2) (12). The latter represents, to our knowledge, the first use of ∆Phe—a rigid “β-breaker” with extended electronic conjugation between its side chain and main chain (SI Appendix, Fig. S1)—as a probe of induced fit in macromolecular recognition. In addition, a fourth analog, active but with anomalous flexibility in the B chain (5, 6) (Analog Modification Templates* Rationale 1 d-AlaB20, d-AlaB23 Insulin; KP-insulin Locked β-turn 2 ∆PheB25 KP-insulin; DKP-insulin β-breaker at B25 3 ∆PheB24 KP-insulin; DKP-insulin β-breaker at B24 4 GlyB24 KP-insulin; DKP-insulin Destabilized hinge