Somatic uniparental disomy mitigates the most damaging EFL1 allele combination in Shwachman-Diamond syndrome.

Shwachman-Diamond syndrome (SDS; OMIM #260400) is caused by variants in SBDS (Shwachman-Bodian-Diamond syndrome gene), which encodes a protein that plays an important role in ribosome assembly. Recent reports suggest that recessive variants in EFL1 are also responsible for SDS. However, the precise genetic mechanism that leads to EFL1-induced SDS remains incompletely understood. Here we present 3 unrelated Korean SDS patients who carry biallelic pathogenic variants in EFL1 with biased allele frequencies, resulting from a bone marrow-specific somatic uniparental disomy in chromosome 15. The recombination events generated cells that were homozygous for the relatively milder variant, allowing for the evasion of catastrophic physiologic consequences. However, the milder EFL1 variant was still solely able to impair 80S ribosome assembly and induce SDS features in cell line and animal models. The loss of EFL1 resulted in a pronounced inhibition of terminal oligopyrimidine element-containing ribosomal protein transcript 80S assembly. Therefore, we propose a more accurate pathogenesis mechanism of EFL1 dysfunction that eventually leads to aberrant translational control and ribosomopathy.

Examination of abiotic cofactor assembly in photosynthetic biomimetics: site-specific stereoselectivity in the conjugation of a ruthenium(II) tris(bipyridine) photosensitizer to a multi-heme protein.

To understand design principles for assembling photosynthetic biohybrids that incorporate precisely-controlled sites for electron injection into redox enzyme cofactor arrays, we investigated the influence of chirality in assembly of the photosensitizer ruthenium(II)bis(2,2'-bipyridine)(4-bromomethyl-4'-methyl-2,2'-bipyridine), Ru(bpy)2(Br-bpy), when covalently conjugated to cysteine residues introduced by site-directed mutagenesis in the triheme periplasmic cytochrome A (PpcA) as a model biohybrid system. For two investigated conjugates that show ultrafast electron transfer, A23C-Ru and K29C-Ru, analysis by circular dichroism spectroscopy, CD, demonstrated site-specific chiral discrimination as a factor emerging from the close association between [Ru(bpy)3]2+ and heme cofactors. CD analysis showed the A23C-Ru and K29C-Ru conjugates to have distinct, but opposite, stereoselectivity for the Λ and Δ-Ru(bpy)2(Br-bpy) enantiomers, with enantiomeric excesses of 33.1% and 65.6%, respectively. In contrast, Ru(bpy)2(Br-bpy) conjugation to a protein site with high flexibility, represented by the E39C-Ru construct, exhibited a nearly negligible chiral selectivity, measured by an enantiomeric excess of 4.2% for the Λ enantiomer. Molecular dynamics simulations showed that site-specific stereoselectivity reflects steric constraints at the conjugating sites and that a high degree of chiral selectivity correlates to reduced structural disorder for [Ru(bpy)3]2+ in the linked assembly. This work identifies chiral discrimination as means to achieve site-specific, precise geometric positioning of introduced photosensitizers relative to the heme cofactors in manner that mimics the tuning of cofactors in photosynthesis.

Detection and quantification of transition metal leaching in metal affinity chromatography with hydroxynaphthol blue.

The widespread use of immobilized metal-affinity chromatography (IMAC) for fast and efficient purification of recombinant proteins has brought potentially toxic transition elements into common laboratory usage. However, there are few studies on the leaching of metal from the affinity resin, such as nickel-nitrilotriacetic acid (Ni-NTA), with possible deleterious impact on the biological activity. This is of particular importance when reducing or chelating eluants stronger than imidazole are used. We present a detailed study of hydroxynaphthol blue (HNB) as an indicator of several divalent metal cations, but with emphasis on Ni2+, clarifying and correcting many errors and ambiguities in the older literature on this dye compound. The assay is simple and sensitive and many metals, notably Ni2+, Zn2+, Cu2+, Pb2+, Fe2+, Co2+, and Al3+, can be readily detected and quantified at concentrations down to 15-50 nM (1-5 ppb) at neutral pH and in most commonly used buffers using spectroscopic equipment available in typical biochemistry research labs. Using this method, we show that significant amounts of Ni2+ (up to 20 mM) are co-purified with a target protein (cytochrome bc1 complex) when histidine is used to elute from Ni-NTA resin.

Molecular interactions between Geobacter sulfurreducens triheme cytochromes and the redox active analogue for humic substances.

The bacterium Geobacter sulfurreducens can transfer electrons to quinone moieties of humic substances or to anthraquinone-2,6-disulfonate (AQDS), a model for the humic acids. The reduced form of AQDS (AH2QDS) can also be used as energy source by G. sulfurreducens. Such bidirectional utilization of humic substances confers competitive advantages to these bacteria in Fe(III) enriched environments. Previous studies have shown that the triheme cytochrome PpcA from G. sulfurreducens has a bifunctional behavior toward the humic substance analogue. It can reduce AQDS but the protein can also be reduced by AH2QDS. Using stopped-flow kinetic measurements we were able to demonstrate that other periplasmic members of the PpcA-family in G. sulfurreducens (PpcB, PpcD and PpcE) also showed the same behavior. The extent of the electron transfer is thermodynamically controlled favoring the reduction of the cytochromes. NMR spectra recorded for 13C,15N-enriched samples in the presence increasing amounts of AQDS showed perturbations in the chemical shift signals of the cytochromes. The chemical shift perturbations on cytochromes backbone NH and 1H heme methyl signals were used to map their interaction regions with AQDS, showing that each protein forms a low-affinity binding complex through well-defined positive surface regions in the vicinity of heme IV (PpcB, PpcD and PpcE) and I (PpcE). Docking calculations performed using NMR chemical shift perturbations allowed modeling the interactions between AQDS and each cytochrome at a molecular level. Overall, the results obtained provided important structural-functional relationships to rationalize the microbial respiration of humic substances in G. sulfurreducens.

Piezo-, elasto- and acousto-optic properties of Tl3AsS4 crystals.

Complete matrices of piezo-optic and elasto-optic tensors are experimentally determined for Tl3AsS4 crystals. It is revealed that the piezo-optic coefficients are very high, ∼10-11 N/m2 in the order of magnitude. This implies that Tl3AsS4 can be referred to the best piezo-optic materials. The same concerns the elasto-optic coefficients, of which absolute values are in the interval 0.28-0.54. It is also found that, at the anisotropic and isotropic interactions with the slowest transverse and longitudinal acoustic waves, the acousto-optic figure of merit reaches extremely high values (1.99×10-12 s3/kg and 9.45×10-13 s3/kg, respectively). In other words, the Tl3AsS4 crystals can be referred to as one of the best acousto-optic materials for the visible and infrared spectral ranges.

The Disulfide Bonds within BST-2 Enhance Tensile Strength during Viral Tethering.

Human BST-2/tetherin is a host factor that inhibits the release of enveloped viruses, including HIV-1, HIV-2, and SIV, from the cell surface by tethering viruses to the host cell membrane. BST-2 has an α-helical ectodomain that forms disulfide-linked dimers between two monomers forming a coiled coil. The ectodomain contains three cysteine residues that can participate in disulfide bond formation and are critical for viral tethering. The role of the disulfides in viral tethering is unknown but proposed to be for maintaining the dimer. We explored the role of the disulfides in the structure of BST-2 using experimental, biophysical methods. To understand the role of the disulfides in viral tethering, we used a new approach in viral tethering, steered molecular dynamics. We find that the disulfides coordinate the unfolding of the BST-2 monomers, which adds tensile strength to the coiled coil. Structural differences between oxidized and reduced BST-2 are apparent during unfolding, showing the monomers slide past each other in the absence of the disulfides. We found no evidence to support dissociation of the dimer upon reduction of the disulfide bonds. Moreover, the structure of BST-2 in the absence of the disulfides is similar to that of the oxidized form of BST-2, supporting previous X-ray crystallography and cellular work that showed the disulfides are not required for expression of BST-2. These data provide new insights into viral tethering by using novel techniques in the analysis of BST-2 to give amino acid level insight into functions of BST-2.

Molecular interaction studies revealed the bifunctional behavior of triheme cytochrome PpcA from Geobacter sulfurreducens toward the redox active analog of humic substances.

Humic substances (HS) constitute a significant fraction of natural organic matter in terrestrial and aquatic environments and can act as terminal electron acceptors in anaerobic microbial respiration. Geobacter sulfurreducens has a remarkable respiratory versatility and can utilize the HS analog anthraquinone-2,6-disulfonate (AQDS) as a terminal electron acceptor or its reduced form (AH2QDS) as an electron donor. Previous studies set the triheme cytochrome PpcA as a key component for HS respiration in G. sulfurreducens, but the process is far from fully understood. In this work, NMR chemical shift perturbation measurements were used to map the interaction region between PpcA and AH2QDS, and to measure their binding affinity. The results showed that the AH2QDS binds reversibly to the more solvent exposed edge of PpcA heme IV. The NMR and visible spectroscopies coupled to redox measurements were used to determine the thermodynamic parameters of the PpcA:quinol complex. The higher reduction potential of heme IV (-127mV) compared to that of AH2QDS (-184mV) explains why the electron transfer is more favorable in the case of reduction of the cytochrome by the quinol. The clear evidence obtained for the formation of an electron transfer complex between AH2QDS and PpcA, combined with the fact that the protein also formed a redox complex with AQDS, revealed for the first time the bifunctional behavior of PpcA toward an analog of the HS. Such behavior might confer selective advantage to G. sulfurreducens, which can utilize the HS in any redox state available in the environment for its metabolic needs.

Characterization of the structure and catalytic activity of Legionella pneumophila VipF.

The pathogenic bacteria Legionella pneumophila is known to cause Legionnaires' Disease, a severe pneumonia that can be fatal to immunocompromised individuals and the elderly. Shohdy et al. identified the L. pneumophila vacuole sorting inhibitory protein VipF as a putative N-acetyltransferase based on sequence homology. We have characterized the basic structural and functional properties of VipF to confirm this original functional assignment. Sequence conservation analysis indicates two putative CoA-binding regions within VipF. Homology modeling and small angle X-ray scattering suggest a monomeric, dual-domain structure joined by a flexible linker. Each domain contains the characteristic beta-splay motif found in many acetyltransferases, suggesting that VipF may contain two active sites. Docking experiments suggest reasonable acetyl-CoA binding locations within each beta-splay motif. Broad substrate screening indicated that VipF is capable of acetylating chloramphenicol and both domains are catalytically active. Given that chloramphenicol is not known to be N-acetylated, this is a surprising finding suggesting that VipF is capable of O-acetyltransferase activity. Proteins 2016; 84:1422-1430. © 2016 Wiley Periodicals, Inc.

Evidence for interaction between the triheme cytochrome PpcA from Geobacter sulfurreducens and anthrahydroquinone-2,6-disulfonate, an analog of the redox active components of humic substances.

The bacterium Geobacter sulfurreducens displays an extraordinary respiratory versatility underpinning the diversity of electron donors and acceptors that can be used to sustain anaerobic growth. Remarkably, G. sulfurreducens can also use as electron donors the reduced forms of some acceptors, such as the humic substance analog anthraquinone-2,6-disulfonate (AQDS), a feature that confers environmentally competitive advantages to the organism. Using UV-visible and stopped-flow kinetic measurements we demonstrate that there is electron exchange between the triheme cytochrome PpcA from Gs and AQDS. 2D-(1)H-(15)N HSQC NMR spectra were recorded for (15)N-enriched PpcA samples, in the absence and presence of AQDS. Chemical shift perturbation measurements, at increasing concentration of AQDS, were used to probe the interaction region and to measure the binding affinity of the PpcA-AQDS complex. The perturbations on the NMR signals corresponding to the PpcA backbone NH and heme substituents showed that the region around heme IV interacts with AQDS through the formation of a complex with a definite life time in the NMR time scale. The comparison of the NMR data obtained for PpcA in the presence and absence of AQDS showed that the interaction is reversible. Overall, this study provides for the first time a clear illustration of the formation of an electron transfer complex between AQDS and a G. sulfurreducens triheme cytochrome, shedding light on the electron transfer pathways underlying the microbial oxidation of humics.

Acoustic anisotropy of acoustooptic TI(3)AsS(4) crystals.

We present comprehensive experimental measurements and analysis of anisotropy of the acoustic wave velocities for TI(3)AsS(4) crystals, including the obliquity and nonorthogonality of the acoustic waves, and the deviations from purely longitudinal and transverse polarization types. We have found that the crystals under analysis are characterized by rather low transverse wave velocities v(23) and v(32), which are both equal to 630 m/s. It is shown that the efficiency of acoustooptic (AO) interactions in TI(3)AsS(4) can be notably increased when providing anisotropic interaction with the slowest transverse acoustic wave. Under the previously mentioned conditions, the AO figure-of-merit can be estimated to be extremely high, i.e., approximately 3×10(-12) s(3)/kg.

Multimerization of solution-state proteins by tetrakis(4-sulfonatophenyl)porphyrin.

Surface binding and interactions of anionic porphyins bound to cationic proteins have been studied for nearly three decades and are relevant as models for protein surface molecular recognition and photoinitiated electron transfer. However, interpretation of data in nearly all reports explicitly or implicitly assumed interaction of porphyrin with monodisperse proteins in solutions. In this report, using small-angle X-ray scattering with solution phase samples, we demonstrate that horse heart cytochrome (cyt) c, triheme cytochrome c7 PpcA from Geobacter sulfurreducens, and hen egg lysozyme multimerize in the presence of zinc tetrakis(4-sulfonatophenyl)porphyrin (ZnTPPS). Multimerization of cyt c showed a pH dependence with a stronger apparent binding affinity under alkaline conditions and was weakened in the presence of a high salt concentration. Ferric-cyt c formed complexes larger than those formed by ferro-cyt c. Free base TPPS and FeTPPS facilitated formation of complexes larger than those of ZnTPPS. No increase in protein aggregation state for cationic proteins was observed in the presence of cationic porphyrins. All-atom molecular dynamics simulations of cyt c and PpcA with free base TPPS corroborated X-ray scattering results and revealed a mechanism by which the tetrasubstituted charged porphyrins serve as bridging ligands nucleating multimerization of the complementarily charged protein. The final aggregation products suggest that multimerization involves a combination of electrostatic and hydrophobic interactions. The results demonstrate an overlooked complexity in the design of multifunctional ligands for protein surface recognition.

Domain structure for an amorphous iridium-oxide water-oxidation catalyst characterized by X-ray pair distribution function analysis.

The domain structure of an amorphous, "blue layer" iridium-oxide water-oxidation catalyst film (BL) electrodeposited from the soluble precursor complex, [Cp*Ir(H2O)3]SO4, was characterized by X-ray pair distribution function (PDF) analysis. The results show that the experimental PDF can be fit remarkably well using a single Ir5O22 cluster extracted from the rutile lattice. The model includes distortions that indicate the presence of Ir(µ-O)3Ir or distorted Ir(µ-O)2Ir substructures, and hence deviations from a rutile structure. The five Ir atom cluster is suggested to represent the population-averaged distribution of metal-oxo clusters in the film. BL is found to be distinguished from other amorphous film water-oxidation catalysts because of the remarkably small domain size and homogeneity. As such, the blue layer catalyst provides a model for investigating ligand-determined metal-oxide cluster assembly and catalyst mechanism.

Structure-function analyses of solar fuels catalysts using in situ X-ray scattering.

This tutorial review illustrates opportunities for the resolution of structure-function relationships to aid in the development of new materials for solar energy conversion using a combination of spectroscopy and catalysis measurements with X-ray scattering analyses to provide in situ structural characterization of solar fuels catalysts. As an example, the use of molecular cobaloxime catalysts in bimolecular and supramolecular photocatalysis schemes for proton reduction is briefly reviewed. These highlight the need to develop new modular, hierarchical, self-healing supramolecular architectures for solar fuels catalysis. Examples of the X-ray scattering structural analysis of amorphous materials in the context of photocatalytic function are discussed in detail.

Characterization of an amorphous iridium water-oxidation catalyst electrodeposited from organometallic precursors.

Upon electrochemical oxidation of the precursor complexes [Cp*Ir(H(2)O)(3)]SO(4) (1) or [(Cp*Ir)(2)(OH)(3)]OH (2) (Cp* = pentamethylcyclopentadienyl), a blue layer of amorphous iridium oxide containing a carbon admixture (BL) is deposited onto the anode. The solid-state, amorphous iridium oxide material that is formed from the molecular precursors is significantly more active for water-oxidation catalysis than crystalline IrO(2) and functions as a remarkably robust catalyst, capable of catalyzing water oxidation without deactivation or significant corrosion for at least 70 h. Elemental analysis reveals that BL contains carbon that is derived from the Cp* ligand (∼ 3% by mass after prolonged electrolysis). Because the electrodeposition of precursors 1 or 2 gives a highly active catalyst material, and electrochemical oxidation of other iridium complexes seems not to result in immediate conversion to iridium oxide materials, we investigate here the nature of the deposited material. The steps leading to the formation of BL and its structure have been investigated by a combination of spectroscopic and theoretical methods. IR spectroscopy shows that the carbon content of BL, while containing some C-H bonds intact at short times, is composed primarily of components with C═O fragments at longer times. X-ray absorption and X-ray absorption fine structure show that, on average, the six ligands to iridium in BL are likely oxygen atoms, consistent with formation of iridium oxide under the oxidizing conditions. High-energy X-ray scattering (HEXS) and pair distribution function (PDF) analysis (obtained ex situ on powder samples) show that BL is largely free of the molecular precursors and is composed of small, <7 Å, iridium oxide domains. Density functional theory (DFT) modeling of the X-ray data suggests a limited set of final components in BL; ketomalonate has been chosen as a model fragment because it gives a good fit to the HEXS-PDF data and is a potential decomposition product of Cp*.

Detection of a charge-separated catalyst precursor state in a linked photosensitizer-catalyst assembly.

We have designed two new supramolecular assemblies based on Co(ii)-templated coordination of Ru(bpy)3(2+) (bpy = 2,2'-bipyridyl) analogues as photosensitizers and electron donors to a cobaloxime macrocycle, which are of interest as proton reduction catalysts. The self-assembled photocatalyst precursors were structurally characterized by Co K-edge X-ray absorption spectroscopy and solution-phase X-ray scattering. Visible light excitation of one of the assemblies has yielded instantaneous electron transfer and charge separation to form a transient Co(i) state which persists for 26 ps. The development of a linked photosensitizer-cobaloxime architecture supporting efficient Co(i) charge transfer is significant since it is mechanistically critical as the first photo-induced electron transfer step for hydrogen production, and has not been detected in previous photosensitizer-cobaloxime linked dyad assemblies. X-band EPR spectroscopy has revealed that the Co(ii) centres of both assemblies are high spin, in contrast to most previously described cobaloximes, and likely plays an important role in facilitating photoinduced charge separation. Based on the results obtained from ultrafast and nanosecond transient absorption optical spectroscopies, we propose that charge recombination occurs through multiple ligand states present within the photosensitizer modules. The studies presented here will enhance our understanding of supramolecular photocatalyst assembly and direct new designs for artificial photosynthesis.

Elucidating the domain structure of the cobalt oxide water splitting catalyst by X-ray pair distribution function analysis.

Pair distribution function (PDF) analysis was applied for structural characterization of the cobalt oxide water-splitting catalyst films using high energy X-ray scattering. The catalyst was found to be composed of domains consistent with a cobalt dioxide lattice sheet structure, possibly containing a Co(4)O(4) cubane-type "defect". The analysis identifies the film to consist of domains composed of 13-14 cobalt atoms with distorted coordination geometries that can be modeled by alteration in terminal oxygen atom positions at the domain edge. Phosphate is seen as a disordered component in the films. This work establishes an approach that can be applied to study the structure of in situ cobalt oxide water-splitting film under functional catalytic conditions.

All-atom molecular dynamics simulations reveal significant differences in interaction between antimycin and conserved amino acid residues in bovine and bacterial bc1 complexes.

Antimycin A is the most frequently used specific and powerful inhibitor of the mitochondrial respiratory chain. We used all-atom molecular dynamics (MD) simulations to study the dynamic aspects of the interaction of antimycin A with the Q(i) site of the bacterial and bovine bc(1) complexes embedded in a membrane. The MD simulations revealed considerable conformational flexibility of antimycin and significant mobility of antimycin, as a whole, inside the Q(i) pocket. We conclude that many of the differences in antimycin binding observed in high-resolution x-ray structures may have a dynamic origin and result from fluctuations of protein and antimycin between multiple conformational states of similar energy separated by low activation barriers, as well as from the mobility of antimycin within the Q(i) pocket. The MD simulations also revealed a significant difference in interaction between antimycin and conserved amino acid residues in bovine and bacterial bc(1) complexes. The strong hydrogen bond between antimycin and conserved Asp-228 (bovine numeration) was observed to be frequently broken in the bacterial bc(1) complex and only rarely in the bovine bc(1) complex. In addition, the distances between antimycin and conserved His-201 and Lys-227 were consistently larger in the bacterial bc(1) complex. The observed differences could be responsible for a weaker interaction of antimycin with the bacterial bc(1) complex.

Binding of imidazole to the heme of cytochrome c1 and inhibition of the bc1 complex from Rhodobacter sphaeroides: I. Equilibrium and modeling studies.

We have used imidazole (Im) and N-methylimidazole (MeIm) as probes of the heme-binding cavity of membrane-bound cytochrome (cyt) c(1) in detergent-solubilized bc(1) complex from Rhodobacter sphaeroides. Imidazole binding to cyt c(1) substantially lowers the midpoint potential of the heme and fully inhibits bc(1) complex activity. Temperature dependences showed that binding of Im (K(d) approximately 330 microM, 25 degrees C, pH 8) is enthalpically driven (DeltaH(0) = -56 kJ/mol, DeltaS(0) = -121 J/mol/K), whereas binding of MeIm is 30 times weaker (K(d) approximately 9.3 mM) and is entropically driven (DeltaH(0) = 47 kJ/mol, DeltaS(0)(o) = 197 J/mol/K). The large enthalpic and entropic contributions suggest significant structural and solvation changes in cyt c(1) triggered by ligand binding. Comparison of these results with those obtained previously for soluble cyts c and c(2) suggested that Im binding to cyt c(1) is assisted by formation of hydrogen bonds within the heme cleft. This was strongly supported by molecular dynamics simulations of Im adducts of cyts c, c(2), and c(1), which showed hydrogen bonds formed between the N(delta)H of Im and the cyt c(1) protein, or with a water molecule sequestered with the ligand in the heme cleft.

Binding of imidazole to the heme of cytochrome c1 and inhibition of the bc1 complex from Rhodobacter sphaeroides: II. Kinetics and mechanism of binding.

The kinetics of imidazole (Im) and N-methylimidazole (MeIm) binding to oxidized cytochrome (cyt) c(1) of detergent-solubilized bc(1) complex from Rhodobacter sphaeroides are described. The rate of formation of the cyt c(1)-Im complex exhibited three separated regions of dependence on the concentration of imidazole: (i) below 8 mM Im, the rate increased with concentration in a parabolic manner; (ii) above 20 mM, the rate leveled off, indicating a rate-limiting conformational step with lifetime approximately 1 s; and (iii) at Im concentrations above 100 mM, the rate substantially increased again, also parabolically. In contrast, binding of MeIm followed a simple hyperbolic concentration dependence. The temperature dependences of the binding and release kinetics of Im and MeIm were also measured and revealed very large activation parameters for all reactions. The complex concentration dependence of the Im binding rate is not consistent with the popular model for soluble c-type cytochromes in which exogenous ligand binding is preceded by spontaneous opening of the heme cleft, which becomes rate-limiting at high ligand concentrations. Instead, binding of ligand to the heme is explained by a model in which an initial and superficial binding facilitates access to the heme by disruption of hydrogen-bonded structures in the heme domain. For imidazole, two separate pathways of heme access are indicated by the distinct kinetics at low and high concentration. The structural basis for ligand entry to the heme cleft is discussed.

Entropy-Induced Multivalley Band Structures Improve Thermoelectric Performance in p-Cu7P(SxSe1-x)6 Argyrodites.

Searching for novel low-cost and eco-friendly materials for energy conversion is a good way to provide widespread utilization of thermoelectric technologies. Herein, we report the thermal behavior, phase equilibria data, and thermoelectric properties for the promising argyrodite-based Cu7P(SxSe1-x)6 thermoelectrics. Alloying of Cu7PSe6 with Cu7PS6 provides a continuous solid solution over the whole compositional range, as shown in the proposed phase diagram for the Cu7PS6-Cu7PSe6 system. As a member of liquid-like materials, the investigated Cu7P(SxSe1-x)6 solid solutions possess a dramatically low lattice thermal conductivity, as low as ∼0.2-0.3 W m-1 K-1, over the entire temperature range. Engineering the configurational entropy of the material by introducing more elements stabilizes the thermoelectrically beneficial high-symmetry γ-phase and promotes the multivalley electronic structure of the valence band. As a result, a remarkable improvement of the Seebeck coefficient and a reduction of electrical resistivity were observed for the investigated alloys. The combined effect of the extremely low lattice thermal conductivity and enhanced power factor leads to the significant enhancement of the thermoelectric figure of merit ZT up to ∼0.75 at 673 K for the Cu7P(SxSe1-x)6 (x = 0.5) sample with the highest configurational entropy, which is around twice higher compared with the pure selenide and almost four times higher than sulfide. This work not only demonstrates the large potential of Cu7P(SxSe1-x)6 materials for energy conversion but also promotes sulfide argyrodites as earth-abundant and environmentally friendly materials for energy conversion.