No abstract

Recent evidence suggests that the prion protein (PrP) is a copper binding protein. The N-terminal region of human PrP contains four sequential copies of the highly conserved octarepeat sequence PHGGGWGQ spanning residues 60-91. This region selectively binds Cu2+ in vivo. In a previous study using peptide design, EPR, and CD spectroscopy, we showed that the HGGGW segment within each octarepeat comprises the fundamental Cu2+ binding unit [Aronoff-Spencer et al. (2000) Biochemistry 40, 13760-13771]. Here we present the first atomic resolution view of the copper binding site within an octarepeat. The crystal structure of HGGGW in a complex with Cu2+ reveals equatorial coordination by the histidine imidazole, two deprotonated glycine amides, and a glycine carbonyl, along with an axial water bridging to the Trp indole. Companion S-band EPR, X-band ESEEM, and HYSCORE experiments performed on a library of 15N-labeled peptides indicate that the structure of the copper binding site in HGGGW and PHGGGWGQ in solution is consistent with that of the crystal structure. Moreover, EPR performed on PrP(23-28, 57-91) and an 15N-labeled analogue demonstrates that the identified structure is maintained in the full PrP octarepeat domain. It has been shown that copper stimulates PrP endocytosis. The identified Gly-Cu linkage is unstable below pH approximately 6.5 and thus suggests a pH-dependent molecular mechanism by which PrP detects Cu2+ in the extracellular matrix or releases PrP-bound Cu2+ within the endosome. The structure also reveals an unusual complementary interaction between copper-structured HGGGW units that may facilitate molecular recognition between prion proteins, thereby suggesting a mechanism for transmembrane signaling and perhaps conversion to the pathogenic form.

The design and synthesis of molecular receptors able to form stable complexes with guest molecules has been a major challenge of supramolecular chemistry. 1 Association of the receptors, sometimes referred to as molecular tweezers or clips, 2 with guest molecules depends on weak specific interactions such as hydrogen bonding, ion pairing, and dipole-dipole and arene-arene (π-π) interactions in addition to nonspecific van der Waals forces. Since the discovery of fullerenes and related materials the interactions of their curved conjugated carbon networks with properly assembled aromatic rings have been recognized as a significant motif for the formation of inclusion complexes. 3 Buckybowls, bowl-shaped polycyclic aromatic hydrocarbons with carbon networks related to fullerenes, appear to be ideal candidates for molecular receptors with the ability to recognize curved-surface fullerene cages through concave-convex "ball-and-socket" π-π interactions. 4 Corannulene (1) is the smallest and best studied buckybowl. However, even though concave-convex interactions between C 60 (2) and corannulene have been previously proposed in the observed gas-phase formation of [C 60 -1] +1 complex, 5 no experimental evidence exists to unequivocally prove this stereochemical arrangement between buckybowls and fullerenes.

Complexes, Ir(CO)Cl(PR 3 ) 2 2135 2. Addition of Ir 2 (µ-Cl) 2 (η 4 -C 8 H 12 ) 2 to C 60 2144 3. Reaction of (η 5 -C 9 H 7 )Ir(CO)(η 2 -C 8 H 12 ) with C 60 2144 4. Reaction of C 60 with the Hydrogenation Catalyst, RhH(CO)(PPh 3 ) 3 2145 5. Other Additions 2145 6. Redox Reactions 2146 7. Cocrystallizations 2147 H. Platinum, Palladium, and Nickel 2147 1. Addition of M(PR 3 ) 2 Units to Fullerenes 2147 2. Formation of Pd(0) and Pt(0) Polymers 2151 3. Redox Reactions 2152 4.

Solutions of C60, C60O, or C70 and metal complexes of octaethylporphyrin (OEPH2) yield crystals that contain both the fullerene and the porphyrin. The structures of C60·2CoII(OEP)·CHCl3, C60·2ZnII(OEP)·CHCl3, and C60O·2CoII(OEP)·CHCl3 are isomorphous and contain an ordered C60 cage surrounded by two MII(OEP) units. Although there is no covalent bond between the fullerene and porphyrin components, the separation between these units is shorter than normal van der Waals contact. Crystals of C70·CoII(OEP)·C6H6·CHCl3, C70·NiII(OEP)·C6H6·CHCl3, and C70·CuII(OEP)·C6H6·CHCl3 are also isomorphous with an ordered fullerene, but have only one porphyrin/fullerene contact. Crystalline C60·ClFeIII(OEP)·CHCl3 lacks the close face-to-face porphyrin/porphyrin contact that is common to all of the other structures reported here but retains the intimate contact between the porphyrin and the fullerene. In (C120O)·CoII(OEP)·0.6C6H6·0.4CHCl3 the fullerene dimer is enclosed by two CoII(OEP) moieties. Unfortunately disorder in the fullerene portion obscures details of the geometry of the bridging region between the fullerenes.

4] X-ray structural analyses on a Stoe-IPDS diffractometer with Mo,, (i = 0.71073 A): data collection and refinement for C,,,H,,,P,Ag,Te, 1 at 190 K : yellow plate, 0.55 x 0.55 x 0.02 mm, trigonal, space group R3, u =14.255(1). c = 56.896(4)& V = 1 0 0 1 3 ( l ) A 3 , Z = 3,p,.,,, =1.896gcm-', p = 33.30 cm I . 2$,,, = 45.0". 9702 reflections collected, 5062 independent (R,,, = 0.0642) and 4629 observed [F,>4a(Fo)]. The structure was solved by direct methods and refined on F2 using SHELXTL software. Data were corrected for Lorentz and polarization effects. No absorption correction was applied. All Ag. Te. and P atoms were refined anisotropically and hydrogen atoms were not included (177 parameters). Final R = 0.0678 and UR, = 0.1899 with GOF =1.077 and an absolute structure parameter = -0.06 (7). Largest difference peak and hole =1.62 and -0.94 e k ' , respectively. support and Professor A. H. Maki for helpful discussions. [**I We thank the National Science Foundation (grant no. CHE 9321 257) for 1179 ~. Anpeu' c h P m . Inr Ed E n d 1997. 36. N o . I f (3 VCH Verlugsgesellscha/t mbH, 0-69481 Weinheim, 1997 0.570-0833/97/3611-lJ79 $ 17.50+ .50/0

The reaction of 2 equiv of LiC6H3-2,6-Mes2 (Mes = 2,4,6-Me3C6H2−) with GeCl2·dioxane, SnCl2, or PbCl2 in ether solution has resulted in the isolation of rare examples of monomeric, σ-bonded, diaryl derivatives M{C6H3-2,6-Mes2}2 (M = Ge (1), Sn (2), or Pb (3)). The compounds 1−3 are thermally stable, purple, crystalline solids with V-shaped geometries and remarkably wide (ca. 114.5°) interligand bond angles. The monoaryl metal chloride derivatives [M(Cl){C6H3-2,6-Mes2}]2 (M = Ge (4) or Sn (5)) were isolated by treatment of the appropriate dichlorides with either 1 equiv of LiC6H3-2,6-Mes2 or 1 equiv of the diaryls 1 or 2. The orange germanium compound 4 has a dimeric structure in which the monomers are linked by a relatively weak, 2.443(2) Å, Ge−Ge interaction. In sharp contrast, its yellow tin analogue 5 has a dimeric structure in which three-coordinate tin centers are associated by asymmetrically bridging chlorides. The compounds 1−3 constitute a unique, structurally characterized diaryl series for Ge, Sn, and Pb and display evidence of steric crowding that is significantly greater than that observed in previously known σ-bonded diorgano group 14 derivatives. The compounds 4 and 5 are the first fully structurally characterized organometal halide derivatives of Ge or Sn in which the organic ligand is monodentate, purely σ-bonded, and nonchelating.

The synthesis and characterization of several m-terphenyl heavier main group 15 (P, As, Sb, or Bi) dihalides, together with their reduction to give a homologous series of double-bonded dipnictenes, are reported. Reaction of LiC6H3-2,6-Mes2 (Mes = C6H2-2,4,6-Me3) or LiC6H3-2,6-Trip2 (Trip = C6H2-2,4,6-iPr3) with the appropriate trihalide affords 2,6-Mes2H3C6ECl2 (E = As, 1; Sb, 2; Bi, 3) and 2,6-Trip2H3C6ECl2 (E = P, 4; As, 5; Sb, 6; Bi, 7). The compounds 1 − 7 were characterized by 1H and 13C NMR spectroscopy as well as by 31P NMR spectroscopy in the case of 4. In addition, the structures of 3, 5, and 6 were determined. Reduction of the phosphorus species 4 with potassium in hexane gives a mixture of the diphosphene 2,6-Trip2H3C6PPC6H3-2,6-Trip2, 12, and the phosphafluorene species, 1-(2,4,6-triisopropylphenyl)-5,7-diisopropyl-9-phosphafluorene, 11. The compound 11, which results from the insertion of a phosphorus into a C(Ar)−C(i-Pr) bond was synthesized in higher yield by the reduction of 4 with magnesium. The simple reduction of 1 − 4, 6, and 7 with potassium, and of 5 with magnesium, yielded the new series of dipnictenes, 2,6-Mes2H3C6E=EC6H3-2,6-Mes2 (E = As, 8; Sb, 9; Bi, 10) and 2,6-Trip2H3C6E=EC6H3-2,6-Trip2 (E = P, 12; As, 13; Sb, 14a; Bi, 15), as well as the partially reduced species 2,6-Trip2H3C6(Cl)SbSb(Cl)C6H3-2,6-Trip2 (14b). The compounds, which displayed high thermal stability, were characterized by 1H, 13C, and 31P NMR and UV−vis spectroscopy. The structures of 8 − 11, 13, 14a, and 14b were determined. These compounds constitute the first homologous series of dipnictene structures for all the heavier group 15 elements. The E−E bond shortenings observed for the heaviest antimony or bismuth derivatives lead to the conclusion that π overlap is quite important in the fifth- and sixth-period elements of this group.