Biochimica et biophysica acta. Biomembranes最新文献_第5页

Biophysical investigations of the membrane interactions of collagen VI-derived host defense peptides vi型胶原衍生宿主防御肽膜相互作用的生物物理研究。

IF 2.5 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Biomembranes

Pub Date : 2025-12-01 Epub Date: 2025-08-28 DOI: 10.1016/j.bbamem.2025.184448

Kathakali De , Karin Bryder , Christopher Aisenbrey , Matthias Mörgelin , Burkhard Bechinger

Collagen VI is an extracellular matrix protein forming complex microfibrillar networks in connective tissues. Specifically, we focused on its role in innate immunity, in particular on cationic sequence motifs from the α3(VI)-chain, which exhibit strong antibacterial properties against both Gram-positive and Gram-negative bacteria in vitro and in vivo. Cytotoxicity assays revealed minimal to no adverse effects, even at concentrations effective against bacterial pathogens. This favorable safety profile suggests that these antimicrobial peptides selectively target bacterial membranes while sparing host cells, making them promising candidates for therapeutic development.

The membrane structure and interactions of two antimicrobial peptides were investigated in quantitative detail using solid-state NMR, CD and fluorescence spectroscopies. Whereas calcein release was somewhat more pronounced from POPE/POPG 3/1 vesicles when compared to POPC/30 % cholesterol, this activity is about two orders of magnitude increased when POPC/POPG 3/1 liposomes are investigated. This pronounced lipid dependence was reproduced with magainin 2, a well-known linear cationic AMP. In lipid titration experiments both collagen-derived peptides showed a transition from predominantly random coil to helical conformations. Quantitative evaluation of membrane association required the presence of PEG-lipids which are known to prevent the agglutination of POPE/POPG 3/1 liposomes. A dissociation constant in the 260 μM range was observed for GVR28 while the binding isotherms reveal an intermediate state when SFV33 associates with bacterial membranes. ²H solid-state NMR reveals considerable membrane disorder of the deuterated PG palmitoyl chain in POPE/POPG membranes. The ensemble of biophysical data suggests two distinct modes of action for the collagen derived peptides.

胶原VI是一种细胞外基质蛋白，在结缔组织中形成复杂的微纤维网络。具体来说，我们关注的是它在先天免疫中的作用，特别是α3（VI）链上的阳离子序列基序，它在体外和体内对革兰氏阳性和革兰氏阴性细菌都表现出很强的抗菌特性。细胞毒性试验显示，即使在对细菌病原体有效的浓度下，也几乎没有副作用。这种良好的安全性表明，这些抗菌肽选择性地靶向细菌膜，同时保留宿主细胞，使其成为治疗开发的有希望的候选者。利用固体核磁共振、CD和荧光光谱对两种抗菌肽的膜结构和相互作用进行了定量详细研究。与POPC/30 %胆固醇相比，POPE/POPG 3/1囊泡释放的钙黄蛋白更为明显，而当研究POPC/POPG 3/1脂质体时，这种活性增加了大约两个数量级。这种明显的脂质依赖性在magainin 2（一种众所周知的线性阳离子AMP）中得到了再现。在脂质滴定实验中，两种胶原来源的肽都表现出从主要随机线圈到螺旋构象的转变。膜关联的定量评估需要peg -脂质的存在，已知peg -脂质可以防止POPE/POPG 3/1脂质体的凝集。GVR28的解离常数在260 μM范围内，而结合等温线显示SFV33与细菌膜结合时处于中间状态。2H固态核磁共振显示，在POPE/POPG膜中氘化PG棕榈酰链存在明显的膜无序性。综合生物物理数据表明胶原衍生肽有两种不同的作用模式。

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引用次数: 0

Order parameters in membranes: Following Joachim Seelig's path 膜中的有序参数：遵循Joachim Seelig的路径。

IF 2.5 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Biomembranes

Pub Date : 2025-12-01 Epub Date: 2025-08-31 DOI: 10.1016/j.bbamem.2025.184449

Estelle Morvan , Axelle Grélard , Erick J. Dufourc

Following the publication of biological membrane models in the 1970s, Joachim Seelig was the first to experimentally demonstrate the dynamic nature of these membranes. He conducted the first ssNMR experiments to measure the order parameters of the CD (²H) bond of lipids deuterium-labelled, showing a fairly fluid membrane interior. Since then, the order parameters of the CD, CH and CC bonds have been measured. They can be used to describe the dynamics of membranes on several space and time scales: intramolecular (Å/ns-ps), molecular (nm/ns–100 ns) and collective (membrane deformations, μm/μs). The profile of CD, CH, CC order parameters across the membrane bilayer allows us to describe the lipid membrane as being very rigid at the glycerol and chain levels and very fluid at its center and surface. This is true for lipid chains carrying double bonds, rings or branched methyl groups. Bipolar lipids that span the entire membrane do not have a very fluid membrane interior. Sterols modulate membrane dynamics, increasing order parameters in the fluid phase and decreasing them in the gel phases. They can be described as regulators of membrane dynamics, as they maintain the membrane in a dynamic state that varies very little when environmental factors change (temperature, pH, etc.). The description of order parameters by statistical mechanics allows the length of the chains, the thickness of the bilayer and the membrane elastic constants to be calculated accurately. The surface area of each lipid in the membrane can also be calculated from the plateau of order parameters (positions C3-C10):

(A_{L}) = 83 (1 - (S_{CD}^{plat}))

.

随着20世纪70年代生物膜模型的发表，Joachim Seelig是第一个通过实验证明这些膜的动态特性的人。他进行了第一次ssNMR实验，测量了氘标记的脂质CD （2H）键的有序参数，显示出相当流体的膜内部。从那时起，CD， CH和CC键的有序参数被测量。它们可以用来描述膜在几个空间和时间尺度上的动力学：分子内（Å/ns-ps），分子（nm/1-100 ns）和集体（膜变形，μm/μs）。CD， CH， CC在膜双分子层上的顺序参数的轮廓使我们能够将脂质膜描述为在甘油和链水平上非常坚硬，在其中心和表面非常流动。这对于带有双键、环或支链甲基的脂链来说是正确的。跨越整个膜的双极脂质没有一个非常流体的膜内部。甾醇调节膜动力学，增加流体相的序参量，减少凝胶相的序参量。它们可以被描述为膜动力学的调节器，因为当环境因素（温度、pH等）发生变化时，它们使膜保持在动态状态，变化很小。用统计力学方法描述的有序参数可以精确计算链的长度、双层膜的厚度和膜的弹性常数。膜中各脂类的表面积也可由序参数平台（位置C3-C10）计算得到：AL=831-SCDplat。

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引用次数: 0

Steady dimer formation by the S31N mutant of influenza A virus M2 protein in living cell membranes 甲型流感病毒M2蛋白S31N突变体在活细胞膜上稳定二聚体的形成

IF 2.5 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Biomembranes

Pub Date : 2025-12-01 Epub Date: 2025-09-09 DOI: 10.1016/j.bbamem.2025.184456

Kenichi Kawano , Tyuji Hoshino , Yoshiaki Yano , Katsumi Matsuzaki

The integral matrix protein M2 of the influenza A virus (H3N2) has been proposed to form a proton-selective channel, and is a target of the antiviral drug amantadine hydrochloride (Am). A significant increase in the number of drug-resistant strains containing the predominant M2-S31N mutant have emerged. We have previously developed a stoichiometric analysis of oligomeric states of membrane proteins by utilizing a coiled-coil method and fluorescence resonance energy transfer phenomenon and demonstrated that full-length M2-WT proteins in living cells formed a dimer at neutral pH, which was converted to a tetramer at acidic pH. In the present study, we revealed that the M2-S31N mutant stably formed dimers independent of pH, which was stabilized by multiple interactions between the protomers. We also found that neither the channel activity nor the oligomeric state of S31N were affected by Am. Molecular dynamics (MD) simulations revealed that Asn31 and Ile35 are involved in proton conduction via steady interactions with cholesterol. These results indicate that Am resistance could be attributed to a change in the arrangement of helices interfering with drug binding.

甲型流感病毒（H3N2）的积分基质蛋白M2已被提出形成质子选择通道，并且是抗病毒药物盐酸金刚烷胺（Am）的靶点。含有主要M2-S31N突变体的耐药菌株数量显著增加。我们之前利用螺旋法和荧光共振能量转移现象对膜蛋白的寡聚物状态进行了化学计量分析，并证明了活细胞中全长M2-WT蛋白在中性pH下形成二聚体，在酸性pH下转化为四聚体。在本研究中，我们发现M2-S31N突变体稳定形成二聚体，不依赖于pH，并通过原聚体之间的多重相互作用来稳定。我们还发现，Am对S31N的通道活性和低聚态都没有影响。分子动力学（MD）模拟显示Asn31和Ile35通过与胆固醇的稳定相互作用参与质子传导。这些结果表明，Am耐药可能归因于干扰药物结合的螺旋排列的变化。

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引用次数: 0

Daptomycin membrane activity is modulated by the localized interplay between calcium ions and phospholipids in monolayers and bilayers containing a lysyl-phosphatidylglycerol analogue 达托霉素膜的活性是由钙离子与含有赖氨酸磷脂酰甘油类似物的单层和双层磷脂之间的局部相互作用调节的。

IF 2.5 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Biomembranes

Pub Date : 2025-12-01 Epub Date: 2025-09-08 DOI: 10.1016/j.bbamem.2025.184452

Maria Hoernke , Shuai Shi , Alasdair T.M. Hubbard , Nina Geringer , Fabio Strati , Chen Shen , Christian Wölk , Richard D. Harvey

Using the stable synthetic analogue 3-aza-dehydroxylysyl-phosphatidylglycerol (3adLPG), the putative role of native staphylococcal LPG in inhibiting the antibiotic daptomycin from binding to its target phosphatidylglycerol (PG), was investigated with respect to interfacial interactions between these lipids, daptomycin, and calcium ions. The influence of lipid monolayer/bilayer composition and interfacial ion concentrations upon the structure and integrity of model membranes were probed after daptomycin challenge using a combination of surface x-ray scattering techniques and fluorescence assays. In models representing the membrane composition of the daptomycin susceptible phenotype consisting of PG/3adLPG in a 7:3 M ratio, calcium ions drive the formation of two separate phases; Ca²⁺ cross-linked PG/PG pairs and PG/3adLPG ion pairs. Daptomycin is able to bind directly to the lipids in the PG/PG phase and increases the amount of interfacial Ca²⁺ ions to a level sufficient to displace 3adLPG from ion pairs with PG, and thus binds to its target PG. In bilayers with mixed chain lipids, daptomycin leads to pronounced membrane perturbations and enhanced permeability. Sequestering all of the available PG into PG/3adLPG ion pairs, therefore, would represent a putative daptomycin non-susceptible membrane. Daptomycin binding and the extent of subsequent lipid structural changes are reduced in these membranes. This implies that in bacteria, native LPG biosynthesis would need to ensure either an equivalence or an excess in relation to membrane PG content, in order for this mechanism alone to significantly contribute to daptomycin resistance.

利用稳定的合成类似物3-氮杂-去羟基赖基-磷脂酰甘油（3adLPG），研究了天然葡萄球菌LPG在抑制抗生素达托霉素与其靶磷脂酰甘油（PG）结合中的作用，并研究了这些脂质、达托霉素和钙离子之间的界面相互作用。利用表面x射线散射技术和荧光分析相结合的方法，研究了脂质单层/双层组成和界面离子浓度对达托霉素激发后模型膜结构和完整性的影响。在代表由PG/3adLPG以7:3 M比例组成的达托霉素敏感表型的膜组成模型中，钙离子驱动两个独立相的形成；Ca2+交联的PG/PG对和PG/3adLPG对。达托霉素能够直接与PG/PG相的脂质结合，并将界面Ca2+离子的数量增加到足以取代与PG离子对中的3adLPG的水平，从而与目标PG结合。在混合链脂质的双层中，达托霉素导致明显的膜扰动和通透性增强。因此，将所有可用的PG隔离到PG/3adLPG离子对中，将代表假定的达托霉素不敏感膜。达托霉素的结合和随后脂质结构改变的程度在这些膜中减少。这意味着，在细菌中，原生液化石油气生物合成需要确保与膜PG含量相当或过量，才能使这一机制单独显著促进达托霉素耐药性。

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引用次数: 0

Complexes of star-shaped block copolymers of poly(2-alkyl-2-oxazine)s and curcumin can affect lipid bilayers mimicking biomembranes 聚（2-烷基-2-氧嗪）s和姜黄素的星形嵌段共聚物配合物可以影响模拟生物膜的脂质双层

IF 2.5 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Biomembranes

Pub Date : 2025-12-01 Epub Date: 2025-08-22 DOI: 10.1016/j.bbamem.2025.184443

Svetlana S. Efimova , Vera A. Martynyuk , Nina D. Kozina , Tatyana Y. Kirila , Alexander P. Filippov , Olga S. Ostroumova

Poly(2-alkyl-2-oxazine)s (PAlOz) are promising tools for developing delivery systems due to their high biocompatibility, resistance to enzyme hydrolysis, and ability to degrade in biological environments. Here, we investigated the effects of hexaaza[2₆]cyclophane (CPh6), poly(2-methyl-2-oxazine) (PMedOz), a block copolymer of poly(2-ethyl-2-oxazine) (PEtOz) and poly(2-isopropyl-2-oxazine) (PiPrOz), star-shaped block copolymers with six PAlOz arms and a CPh6 branching center (CPh6-PAlOz), and the complexes of all these macromolecules with curcumin on lipid bilayers mimicking the membranes of normal and cancer cells. Curcumin alone demonstrated a pronounced ability to reduce the boundary potential of lipid bilayers composed of phosphatidylcholine or phosphatidylserine, while PMedOz and PEtOz-b-PiPrOz copolymers exhibited either no or weak effects on the electrical properties of biomimetic model membranes. CPh6-PAlOz star-shaped block copolymers were able to interact with K⁺-nonactin. Differential scanning microcalorimetry of the gel-to-liquid crystalline phase transition of membrane lipids indicated that curcumin and all tested macromolecules had more pronounced effects on phosphatidylserine melting than on the phase behavior of phosphatidylcholine. A star-shaped block copolymer with a [PEtOz]/[PiPrOz] ration of 0.8 significantly decreased the melting point of phosphatidylserine. The disordering effects of complexes of curcumin with CPh6, PEtOz-b-PiPrOz copolymers, or the CPh6-PAlOz star-shaped block copolymer with a [PEtOz]/[PiPrOz] ratio of 5 on phosphatidylserine bilayers were less than the algebraic sum of the effects of the polymers and curcumin separately. These data indicate that the carrier cannot be considered an inert matrix that does not affect the biological activity of the transferred active compound, and this should be taken into account when assessing the biological consequences.

聚（2-烷基-2-恶嗪）s （PAlOz）由于其高生物相容性、抗酶水解和在生物环境中降解的能力而成为开发递送系统的有前途的工具。在这里，我们研究了六氮杂环烷（CPh6），聚（2-甲基-2-恶嗪）（PMedOz），聚（2-乙基-2-恶嗪）（PEtOz）和聚（2-异丙基-2-恶嗪）（PiPrOz）的嵌段共聚物，具有六个PAlOz臂和一个CPh6分支中心的星形嵌段共聚物（CPh6-PAlOz），以及所有这些大分子与curcumin的配合物对模拟正常和癌细胞膜的脂质双层的影响。姜黄素可以明显降低磷脂酰胆碱或磷脂酰丝氨酸组成的脂质双分子层的边界电位，而PMedOz和PEtOz-b-PiPrOz共聚物对仿生模型膜的电学性能没有或只有微弱的影响。CPh6-PAlOz星形嵌段共聚物能够与K+-非肌动蛋白相互作用。膜脂凝胶-液晶相变的差示扫描微热法表明，姜黄素和所有被测大分子对磷脂酰丝氨酸熔融的影响比对磷脂酰胆碱相行为的影响更为显著。[PEtOz]/[PiPrOz]比为0.8的星形嵌段共聚物显著降低了磷脂酰丝氨酸的熔点。姜黄素与CPh6、PEtOz-b-PiPrOz共聚物或[PEtOz]/[PiPrOz]比为5的CPh6- paloz星形嵌段共聚物的配合物对磷脂酰丝氨酸双分子层的无序作用小于聚合物与姜黄素各自作用的代数和。这些数据表明，载体不能被认为是不影响转移活性化合物生物活性的惰性基质，在评估生物后果时应考虑到这一点。

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引用次数: 0

SARS-CoV E protein couples asymmetric leaflet thickness and curvature deformations SARS-CoV E蛋白偶联不对称小叶厚度和曲率变形

IF 2.5 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Biomembranes

Pub Date : 2025-12-01 Epub Date: 2025-09-08 DOI: 10.1016/j.bbamem.2025.184447

Jesse W. Sandberg , Grace Brannigan

The Envelope protein (E protein) of SARS-CoVs 1 and 2 has been implicated in the viral budding process and maintaining the spherical shape of the virus, but direct evidence linking the protein to long-range membrane deformation is still lacking. Computational predictions from molecular simulation have offered conflicting results, some showing long-range E-induced membrane curvature and others showing only local deformations. In the present study, we determine the mechanism driving these deformations by modulating the degree of hydrophobic mismatch between protein and membrane. We observe that certain barostat and restraint settings, common in coarse-grained MD simulations, can prevent equilibration of the membrane area. Our results indicate that the E protein does not induce long-range curvature, but does exhibit severe local deformations that are exacerbated by hydrophobic mismatch. These deformations occur in conjunction with local leaflet thickness asymmetry, suggesting asymmetry and curvature couple to reduce the free energy cost of a deformed membrane.

sars - cov 1和2的包膜蛋白（E蛋白）与病毒出芽过程和维持病毒的球形有关，但仍缺乏将该蛋白与远程膜变形联系起来的直接证据。分子模拟的计算预测提供了相互矛盾的结果，一些显示远程e诱导的膜曲率，而另一些只显示局部变形。在目前的研究中，我们通过调节蛋白质和膜之间疏水不匹配的程度来确定驱动这些变形的机制。我们观察到，在粗粒度MD模拟中常见的某些恒压器和约束设置可以阻止膜区域的平衡。我们的研究结果表明，E蛋白不会诱导长程曲率，但确实表现出严重的局部变形，这种变形会因疏水错配而加剧。这些变形与局部小叶厚度不对称一起发生，表明不对称和曲率耦合以减少变形膜的自由能成本。

引用次数: 0

The molecular electrometer at 40 分子静电计在40。

IF 2.5 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Biomembranes

Pub Date : 2025-12-01 Epub Date: 2025-09-08 DOI: 10.1016/j.bbamem.2025.184453

Peter M. Macdonald

In 1987 Seelig and colleagues proposed that the phosphocholine headgroup of phosphatidylcholine behaved as a universal sensor of surface electrostatic charge, both cationic and anionic, in lipid bilayers (J. Seelig, P.M. Macdonald, P.G. Scherer, Phospholipid Head Groups as Sensors of Electric Charge in Membranes. Biochemistry, 26 (1987) 7535–7541.) Changes in the deuterium NMR quadrupolar splitting measured with specifically-deuterated positions within the choline headgroup in response to surface charges were attributed to a conformational change within the phosphocholine group corresponding to a “tilt” of the choline group towards or away from the direction of the bilayer normal as the PN dipole sought to align with the surface electrostatic field. In the ensuing nearly 4 decades this so-called “Molecular Electrometer” concept has become accepted doctrine in membrane science and has been employed to examine lipid bilayer surface electrostatics in a host of situations involving multiple membrane- associating biologically significant factors from ions, to anesthetics, to peptides and proteins. In this review, I describe the history of the science behind the Molecular Electrometer, the evolution of methods for examining the Molecular Electrometer response and provide a survey of its application in the myriad instances of membrane-associating molecules affecting and being affected by surface electrostatics. Lastly, I include an overview of the efforts of molecular dynamics simulations to be guided by and to account for the Molecular Electrometer effect in simulations of lipid bilayers.

1987年，Seelig和同事提出磷脂酰胆碱的磷脂胆碱头基团在脂质双分子层中充当表面静电电荷的通用传感器，包括阳离子和阴离子(J. Seelig， P.M.Macdonald， P.G. Scherer，磷脂头基团作为膜中电荷的传感器。生物化学，26(1987)7535-7541。在胆碱头基团内特定氘化位置测量的氘核磁共振四极分裂的变化，响应于表面电荷，归因于胆碱基团内部的构象变化，对应于胆碱基团向双分子层正态线方向“倾斜”，因为PN偶极子试图与表面静电场对齐。在随后的近40年里，这种所谓的“分子静电计”概念已成为膜科学中公认的原则，并已被用于检查脂质双分子层表面静电，涉及多种与膜相关的生物重要因素，从离子到麻醉剂，到肽和蛋白质。在这篇综述中，我描述了分子静电计背后的科学历史，检查分子静电计响应的方法的演变，并提供了它在无数膜相关分子影响和被表面静电影响的实例中的应用调查。最后，我概述了分子动力学模拟的努力，以指导和解释分子静电计效应在脂质双层模拟中的作用。

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引用次数: 0

Study on the correlation between proton transfer of phenolic hydroxyl groups of 6 flavonoid compounds and their antioxidant activities 6种黄酮类化合物酚羟基质子转移与抗氧化活性的相关性研究

IF 2.5 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Biomembranes

Pub Date : 2025-12-01 Epub Date: 2025-08-19 DOI: 10.1016/j.bbamem.2025.184444

Shuangmei Gong , Changying Yang , Min Li , Xiaobo Li

This study investigated six flavonoids' photophysical properties in various environments, revealing their pKa variations (e.g., quercetin: 7.364 in water vs 9.329 in vesicles) and demonstrating vesicle/liposome systems' protective effects by slowing proton transfer and oxidation. Metal ion complexation occurred preferentially at specific hydroxyl-keto sites (3-OH-4-keto for quercetin/kaempferol, 5-OH-4-keto for apigenin/baicalein), while structural features like phenolic hydroxyl arrangement and double bonds significantly influenced these interactions. Importantly, the work established that vesicular systems provide superior protection against proton transfer and oxidation compared to liposomes.ANS fluorescence quenching studies further characterized their molecular behaviors, providing key insights into flavonoid stabilization mechanisms and pharmacological activity foundations.

本研究研究了6种黄酮类化合物在不同环境下的光物理性质，揭示了它们的pKa变化（例如，槲皮素在水中：7.364比在囊泡中：9.329），并证明了囊泡/脂质体系统通过减缓质子转移和氧化的保护作用。金属离子络合优先发生在特定的羟基酮位点（槲皮素/山奈酚的3- oh -4-酮，芹菜素/黄芩素的5- oh -4-酮），而酚羟基排列和双键等结构特征显著影响这些相互作用。重要的是，这项工作确定了与脂质体相比，囊泡系统提供了更好的保护，防止质子转移和氧化。ANS荧光猝灭研究进一步表征了它们的分子行为，为黄酮类化合物的稳定机制和药理活性基础提供了重要的见解。

引用次数: 0

Improving chemical synthesis and the antimicrobial activity of human defensins through disulfide bond engineering of HBD-3 利用HBD-3的二硫键工程技术提高人体防御素的化学合成和抗菌活性

IF 2.5 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Biomembranes

Pub Date : 2025-12-01 Epub Date: 2025-09-10 DOI: 10.1016/j.bbamem.2025.184457

Aleksandra Walewska , Paulina Kosikowska-Adamus , Anna Wardowska , Grzegorz Bulaj , Emilia Sikorska

Human β-defensins are disulfide-rich peptides that exhibit broad-spectrum antimicrobial activity against bacteria, fungi, and certain viruses, while also exerting immunomodulatory effects. As naturally occurring host defense peptides in the human body, they are less likely to induce adverse immune reactions or toxicity compared to synthetic drugs. Efficient chemical synthesis of cysteine-rich peptides is critical for drug lead optimization studies, yet in many cases is limiting by the low yields of correctly formed disulfide bonds. Herein, we present novel β-defensin 3 analogues with engineered disulfide bonds, designed to simplify and improve oxidative folding while preserving antimicrobial and antifungal activities. Our results suggest that the judicious replacement of cysteine residues with alanines or selenocysteines may facilitate the development of defensin-based drug leads with enhanced pharmacological properties, addressing their therapeutic potential to combat multidrug resistance.

人β-防御素是富含二硫化物的肽，对细菌、真菌和某些病毒具有广谱抗菌活性，同时也具有免疫调节作用。作为人体内天然存在的宿主防御肽，与合成药物相比，它们更不容易引起不良免疫反应或毒性。高效的富含半胱氨酸肽的化学合成对药物先导优化研究至关重要，但在许多情况下，由于正确形成二硫键的产率低而受到限制。在此，我们提出了新的β-防御素3类似物与工程二硫键，旨在简化和改善氧化折叠，同时保持抗菌和抗真菌活性。我们的研究结果表明，明智地用丙氨酸或硒代半胱氨酸替代半胱氨酸残基可能有助于开发基于防御素的药物先导物，增强其药理特性，发挥其治疗多药耐药的潜力。

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引用次数: 0

Small angle neutron scattering study of rhodopsin oligomerization and G-protein coupling in a physiologically relevant lipid membrane 生理相关脂质膜中紫红质寡聚和g蛋白偶联的小角中子散射研究。

IF 2.5 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Biomembranes

Pub Date : 2025-12-01 Epub Date: 2025-09-11 DOI: 10.1016/j.bbamem.2025.184454

Olivier Soubias , Jonathan D. Nickels , Kirk G. Hines , Walter E. Teague , John K. Northup , John Katsaras , Klaus Gawrisch

Although the oligomeric states of G-protein-coupled receptors (GPCRs) and interactions with cognate G proteins are central to their signal transduction capabilities, they remain poorly defined. In this study, we used small-angle neutron scattering (SANS) and a neutron contrast matching approach to elucidate the oligomeric states of the archetypal GPCR, rhodopsin, and its interaction with the G protein transducin (G_t). At a rhodopsin/lipid molar ratio of 1/360, we found that dark-adapted rhodopsin exists as a monomer, a finding consistent with its high functional activity measured upon photoactivation by spectrophotometry and the rate of catalyzed [³⁵S]-GTP-γ-S exchange. Following light activation, we observed that rhodopsin forms a stable 1:1 stoichiometric complex with G_t, the structure of which is consistent with recent cryo-EM data. In contrast, activated rhodopsin in the absence of G_t showed a propensity to form higher order oligomers. This research underscores the concentration-dependent nature of rhodopsin oligomerization and establishes SANS and the ability to produce appropriately contrast-matched samples, as a robust strategy for characterizing integral membrane protein interactions under biologically relevant conditions.

尽管G蛋白偶联受体（gpcr）的寡聚状态和与同源G蛋白的相互作用是其信号转导能力的核心，但它们仍然不明确。在这项研究中，我们使用小角中子散射（SANS）和中子对比匹配方法来阐明原型GPCR，视紫红质的寡聚态及其与G蛋白转导蛋白（Gt）的相互作用。当视紫红质/脂质摩尔比为1/360时，我们发现适应黑暗的视紫红质以单体形式存在，这一发现与分光光度法光活化测量的高功能活性和催化[35S]-GTP-γ-S交换速率一致。在光激活后，我们观察到视紫红质与Gt形成稳定的1:1的化学计量复合物，其结构与最近的冷冻电镜数据一致。相反，在没有Gt的情况下，激活的视紫红质倾向于形成高阶低聚物。本研究强调了视紫红质寡聚化的浓度依赖性，并建立了SANS和产生适当对比匹配样品的能力，作为在生物学相关条件下表征整体膜蛋白相互作用的强大策略。

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引用次数: 0