Serine-cis-proline and Serine-trans-proline Isosteres:  Stereoselective Synthesis of (Z)- and (E)-Alkene Mimics by Still−Wittig and Ireland−Claisen Rearrangements

Wang, Xiaodong J.; Hart, Scott A.; Xu, Bo; Mason, Matthew D.; Goodell, John R.; Etzkorn, Felicia A.

doi:10.1021/jo026663b

Cited by 66 publications

(76 citation statements)

References 39 publications

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“…The final NMR buffer was 30 mM imidazole-4 D -pH 6.6 with 30 mM NaCl, 0.03% NaN 3 , 5 mM DTT-D 10 and 90% H 2 O∕ 10% D 2 O. Side-chain methyls and backbone nuclei were assigned at 295 K using standard triple-resonance experiments (6). The locked inhibitors and substrate FFpSPR were synthesized and purified as described previously (7,8,12 …”

Section: Methodsmentioning

confidence: 99%

“…Pin1 recognizes both conformers. Thus, if and how the two conformers might impose different changes in dynamics remained indeterminate.Etzkorn and coworkers designed peptidomimetic analogs of the Pin1 phospho-serine substrate (FFpSPR) (7,8) (Fig. 1).…”

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confidence: 99%

“…Etzkorn and coworkers designed peptidomimetic analogs of the Pin1 phospho-serine substrate (FFpSPR) (7,8) (Fig. 1).…”

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confidence: 99%

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Stereospecific gating of functional motions in Pin1

Namanja

Wang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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164

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Pin1 is a modular enzyme that accelerates the cis-trans isomerization of phosphorylated-Ser/Thr-Pro (pS/T-P) motifs found in numerous signaling proteins regulating cell growth and neuronal survival. We have used NMR to investigate the interaction of Pin1 with three related ligands that include a pS-P substrate peptide, and two pS-P substrate analogue inhibitors locked in the cis and trans conformations. Specifically, we compared the ligand binding modes and binding-induced changes in Pin1 side-chain flexibility. The cis and trans binding modes differ, and produce different mobility in Pin1. The cis-locked inhibitor and substrate produced a loss of side-chain flexibility along an internal conduit of conserved hydrophobic residues, connecting the domain interface with the isomerase active site. The trans-locked inhibitor produces a weaker conduit response. Thus, the conduit response is stereoselective. We further show interactions between the peptidyl-prolyl isomerase and Trp-Trp (WW) domains amplify the conduit response, and alter binding properties at the remote peptidyl-prolyl isomerase active site. These results suggest that specific input conformations can gate dynamic changes that support intraprotein communication. Such gating may help control the propagation of chemical signals by Pin1, and other modular signaling proteins.allostery | protein dynamics | ligand dynamics | protein evolution P hospho-serine/threonine-proline (pS/T-P) motifs are signaling motifs within intrinsically disordered loops of cell cycle proteins (1). The imide bond between the pS/T and P residues can adopt either the cis or trans conformation. These conformations differ in their susceptibility to kinases and phosphatases that propagate the chemical signals governing the cell cycle. Accordingly, the cell must regulate the cis/trans populations of these pS/T-P motifs to ensure proper signal routing.In this context, the peptidyl-prolyl isomerase Pin1 has emerged as a critical regulator (2, 3). Pin1 is a reversible enzyme that catalyzes the cis-trans isomerization of the pS/T-P imide linkages (2, 3) of other signaling proteins, such as CDC25C, p53, c-Myc, NF-kB, cyclin D1, and tau (3). Pin1 engages when external events, such as S/T (de)-phosphorylation, change the cis-trans equilibrium. Pin1 then catalyzes the cis-trans isomerization, thereby accelerating the approach to the new equilibrium (1).Pin1 is a modular protein of 163 residues consisting of a WW domain (1-39) and a larger peptidyl-prolyl isomerase (PPIase) domain (50-163) (Fig. 1). A flexible linker connects the two domains. Both domains are specific for pS/T-P motifs (1). The WW domain serves as a docking module, whereas catalysis is the sole province of the PPIase domain. Earlier structural studies of Pin1 revealed conformational changes upon substrate interaction, thus motivating flexibility-function studies of Pin1 (4-6). Our previous NMR deuterium relaxation studies of Pin1 mapped the changes in flexibility of methyl-bearing side chains caused by interaction with an establi...

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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Stereospecific gating of functional motions in Pin1

Namanja

Wang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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164

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“…An initial sign of allostery came from NMR titrations of Pin1 with conformationally locked inhibitors, designed by Etzkorn and co-workers (Wang et al 2003; Wang et al 2004). These analogs replace pS in the FFpSPR substrate with alkene isoteres, resulting in non-isomerizable cis and trans-locked competitive inhibitors ( K i, cis = 1.7 ± 0.1 µM, and K i, trans = 40 ± 2 µM (Wang et al 2004)).…”

Section: Hints Of Allostery From Binding and Isomerase Activitymentioning

confidence: 99%

Investigating dynamic interdomain allostery in Pin1

Peng

2015

Biophys Rev

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Signaling proteins often sequester complementary functional sites in separate domains. How do the different domains communicate with one another? An attractive system to address this question is the mitotic regulator, human Pin1 (Lu et al. 1996). Pin-1 consists of two tethered domains: a WW domain for substrate binding, and a catalytic domain for peptidyl-prolyl isomerase (PPIase) activity. Pin1 accelerates the cis-trans isomerization of phospho-Ser/Thr-Pro (pS/T-P) motifs within proteins regulating the cell cycle and neuronal development. The early x-ray (Ranganathan et al. 1997; Verdecia et al. 2000) and solution NMR studies (Bayer et al. 2003; Jacobs et al. 2003) of Pin1 indicated inter- and intradomain motion. We became interested in exploring how such motions might affect interdomain communication, using NMR. Our accumulated results indicate substrate binding to Pin1 WW domain changes the intra/inter domain mobility, thereby altering substrate activity in the distal PPIase domain catalytic site. Thus, Pin1 shows evidence of dynamic allostery, in the sense of Cooper and Dryden (Cooper and Dryden 1984). We highlight our results supporting this conclusion, and summarize them via a simple speculative model of conformational selection.

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“…Now the reduction under Luche conditions provided the desired anti-isomer in excellent yield, albeit at much reduced selectivity. 58 Luthman et al described the diastereoselective reduction of phenylalanine derived enone ester 190 (Scheme 47). 59 Chelation controlled reduction proved to be poorly selective except with the bulky LiAlH(O-tBu) 3 .…”

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confidence: 99%