Lessons from LIMK1 enzymology and their impact on inhibitor design

LIM domain kinase 1 (LIMK1) is a key regulator of actin dynamics. It is thereby a potential therapeutic target for the prevention of fragile X syndrome and amyotrophic lateral sclerosis. Herein, we use X-ray crystallography and activity assays to describe how LIMK1 accomplishes substrate specificity, to suggest a unique ‘rock-and-poke’ mechanism of catalysis and to explore the regulation of the kinase by activation loop phosphorylation. Based on these findings, a differential scanning fluorimetry assay and a RapidFire mass spectrometry activity assay were established, leading to the discovery and confirmation of a set of small-molecule LIMK1 inhibitors. Interestingly, several of the inhibitors were inactive towards the closely related isoform LIMK2. Finally, crystal structures of the LIMK1 kinase domain in complex with inhibitors (PF-477736 and staurosporine, respectively) are presented, providing insights into LIMK1 plasticity upon inhibitor binding

The spectral weight of the Hubbard model through cluster perturbation theory

We calculate the spectral weight of the one- and two-dimensional Hubbard models, by performing exact diagonalizations of finite clusters and treating inter-cluster hopping with perturbation theory. Even with relatively modest clusters (e.g. 12 sites), the spectra thus obtained give an accurate description of the exact results. Thus, spin-charge separation (i.e. an extended spectral weight bounded by singularities) is clearly recognized in the one-dimensional Hubbard model, and so is extended spectral weight in the two-dimensional Hubbard model.Comment: 4 pages, 5 figure

Single-hole dynamics in the half-filled two-dimensional Kondo-Hubbard model

We consider the Kondo lattice model in two dimensions at half filling. In addition to the fermionic hopping integral $t$ and the superexchange coupling $J$ the role of a Coulomb repulsion $U$ in the conduction band is investigated. We find the model to display a magnetic order-disorder transition in the U-J plane with a critical value of J_c which is decreasing as a function of U. The single particle spectral function A(k,w) is computed across this transition. For all values of J > 0, and apart from shadow features present in the ordered state, A(k,w) remains insensitive to the magnetic phase transition with the first low-energy hole states residing at momenta k = (\pm \pi, \pm \pi). As J -> 0 the model maps onto the Hubbard Hamiltonian. Only in this limit, the low-energy spectral weight at k = (\pm \pi, \pm \pi) vanishes with first electron removal-states emerging at wave vectors on the magnetic Brillouin zone boundary. Thus, we conclude that (i) the local screening of impurity spins determines the low energy behavior of the spectral function and (ii) one cannot deform continuously the spectral function of the Mott-Hubbard insulator at J=0 to that of the Kondo insulator at J > J_c. Our results are based on both, T=0 Quantum Monte-Carlo simulations and a bond-operator mean-field theory.Comment: 8 pages, 7 figures. Submitted to PR

Relative Reactivity of the Metal-Amido versus Metal-Imido Bond in Linked Cp-Amido and Half-Sandwich Complexes of Vanadium

Treatment of (η5-C5H4C2H4NR)V(N-t-Bu)Me (R = Me, i-Pr) and CpV(N-p-Tol)(N-i-Pr2)Me (Cp = η5-C5H5) with B(C6F5)3 or [Ph3C][B(C6F5)4] results in formation of the corresponding cations, [(η5-C5H4C2H4NR)V(N-t-Bu)]+ and [CpV(N-p-Tol)(N-i-Pr2)]+. The latter could also be generated as its N,N-dimethylaniline adduct by treatment of the methyl complex with [PhNMe2H][BAr4] (Ar = Ph, C6F5). Instead, the analogous reaction with the linked Cp-amido precursor results in protonation of the imido-nitrogen atom. Sequential cyclometalation of the amide substituents gave cationic imine complexes [(η5-C5H4C2H4NCR'2)V(NH-t-Bu)]+ (R' = H, Me) and methane. Reaction of cationic [(η5-C5H4C2H4NR)V(N-t-Bu)]+ with olefins affords the corresponding olefin adducts, whereas treatment with 1 or 2 equiv of 2-butyne results in insertion of the alkyne into the vanadium-nitrogen single bond, affording the mono- and bis-insertion products [(η5-C5H4C2H4N(i-Pr)C2Me2)V(N-t-Bu)]+ and [(η5-C5H4C2H4N(i-Pr)C4Me4)V(N-t-Bu)]+. The same reaction with the half-sandwich compound [CpV(N-p-Tol)(N-i-Pr2)]+ results in a paramagnetic compound that, upon alcoholysis, affords sec-butylidene-p-tolylamine, suggesting an initial [2+2] cycloaddition reaction. The difference in reactivity between the V-N bond versus the V=N bond was further studied using computational methods. Results were compared to the isoelectronic titanium system CpTi(NH)(NH2). These studies indicate that the kinetic product in each system is derived from a [2+2] cycloaddition reaction. For titanium, this was found as the thermodynamic product as well, whereas the insertion reaction was found to be thermodynamically more favorable in the case of vanadium.

Evaluation of a Simplified Measurement for Low Glomerular Filtration Rates With lndium-111 DTPA

A rapid new method for measuring glomerular filtration rates using 111In diethylenetriamine pentaacetic acid (111In- DTPA) was evaluated with 39 patients who showed marked impairment of renal function (creatinine clearance less than 20 ml/min). A simple, single compartment system was assumed. For comparison, parallel inulin and creatinine clearances were performed. High linear correlations (r = 0.96-0.97) were demonstrated when 111In- DTPA clearances were compared with the standard nonisotopic tests. Initial data indicate that reliable isotopic clearance values could be obtained for low clearances by withdrawing only two blood samples for assay at 6 and 48 hours after isotope injection (without urine assay)

Quasiparticle Dispersion of the 2D Hubbard Model: From an Insulator to a Metal

On the basis of Quantum-Monte-Carlo results the evolution of the spectral weight $A(\vec k, \omega)$ of the two-dimensional Hubbard model is studied from insulating to metallic behavior. As observed in recent photoemission experiments for cuprates, the electronic excitations display essentially doping-independent features: a quasiparticle-like dispersive narrow band of width of the order of the exchange interaction $J$ and a broad valence- and conduction-band background. The continuous evolution is traced back to one and the same many-body origin: the doping-dependent antiferromagnetic spin-spin correlation.Comment: 11 pages, REVtex, 4 figures (in uuencoded postscript format

Shadow band in the one-dimensional large UU Hubbard model

We show that the factorized wave-function of Ogata and Shiba can be used to calculate the $k$ dependent spectral functions of the one-dimensional, infinite $U$ Hubbard model, and of some extensions to finite $U$. The resulting spectral function is remarkably rich: In addition to low energy features typical of Luttinger liquids, there is a well defined band, which we identify as the shadow band resulting from $2k_F$ spin fluctuations. This band should be detectable experimentally because its intensity is comparable to that of the main band for a large range of momenta.Comment: Latex file. 4 pages. Figures upon reques

Operator projection method applied to the single-particle Green's function in the Hubbard model

A new non-perturbative framework for many-body correlated systems is formulated by extending the operator projection method (OPM). This method offers a systematic expansion which enables us to project into the low-energy structure after extracting the higher-energy hierarchy. This method also opens a way to systematically take into account the effects of collective excitations. The Mott-Hubbard metal-insulator transition in the Hubbard model is studied by means of this projection beyond the second order by taking into account magnetic and charge fluctuations in the presence of the high-energy Mott-Hubbard structure. At half filling, the Mott-Hubbard gap is correctly eproduced between the separated two bands. Near half filling, a strongly renormalized low-energy single-particle excitations coexisting with the Mott-Hubbard bands are shown to appear. Signifcance of momentum-dependent self-energy in the results is stressed.Comment: 6 pages, final version to appear in J. Phys. Soc. Jp

Finite temperature spectral-functions of strongly correlated one-dimensional electron systems

The spectral functions of tJ and tJ_{XY} models in the limit of J/t-> 0 and at finite temperatures T>>t are calculated using the spin-charge factorized wave function. We find that the Luttinger-liquid like scaling behavior for a finite system with L sites is restricted below temperatures of the order T = J/L. We also observe weight redistribution in the photoemission spectral function in the energy range t, which is much larger than the temperature.Comment: revtex, 4 pages, 3 eps figure

Quasiparticle structure and coherent propagation in the t−Jz−J⊥t-J_{z}-J_{\perp} model

Numerical studies, from variational calculation to exact diagonalization, all indicate that the quasiparticle generated by introducing one hole into a two-dimensional quantum antiferromagnet has the same nature as a string state in the $t-J_{z}$ model. Based on this observation, we attempt to visualize the quasiparticle formation and subsequent coherent propagation at low energy by studying the generalized $t-J_{z}-J_{\perp}$ model in which we first diagonalize the $t-J_{z}$ model and then perform a {\em degenerate} perturbation in $J_{\perp}$. We construct the quasiparticle state and derive an effective Hamiltonian describing the coherent propagation of the quasiparticle and its interaction with the spin wave excitations in the presence of the N\'{e}el order. We expect that qualitative properties of the quasiparticle remain intact when analytically continuing $J_{\perp}$ from the anisotropic $J_{\perp} < J_{z}$ to the isotropic $J_{\perp} = J_{z}$ limit, despite the fact that the spin wave excitations change from gapful to gapless. Extrapolating to $J_{\perp}=J_{z}$, our quasiparticle dispersion and spectral weight compare well with the exact numerical results for small clusters.Comment: Revised with minor changes and references updated. To appear in Phys. Rev. B., Jan. 1996. 10 pages, The complete PostScript file including figures can be obtained via ftp at ftp://serval.berkeley.edu/tjzjp.ps . It is also posted in the WEB site of Niels Bohr Institute at http://roemer.fys.ku.dk/recent.ht