ACS Bio & Med Chem Au最新文献_第3页

Characterization of a Heme-Binding Radical SAM Enzyme HemW from Moraxella catarrhalis 卡他莫拉菌血红素结合自由基SAM酶HemW的表征

IF 3.5

ACS Bio & Med Chem Au Pub Date : 2026-08-19 Epub Date: 2026-07-08 DOI: 10.1021/acsbiomedchemau.6c00111

Caitlin M. Padgett, Melissa M. Bollmeyer, Kaleb Boswinkle, Anthony T. Iavarone, Valérie de Crécy-Lagard, R. David Britt, Wen Zhu

{"title":"Characterization of a Heme-Binding Radical SAM Enzyme HemW from Moraxella catarrhalis","authors":"Caitlin M. Padgett, Melissa M. Bollmeyer, Kaleb Boswinkle, Anthony T. Iavarone, Valérie de Crécy-Lagard, R. David Britt, Wen Zhu","doi":"10.1021/acsbiomedchemau.6c00111","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.6c00111","url":null,"abstract":"Moraxella catarrhalis isan emerginghuman respiratory pathogen responsible for various infectious diseases.Recent transposon sequencing analysis identified yggW (renamed hemW) as essential for M. catarrhalis growth under iron-limiting conditions,mimicking host-imposed nutritional immunity. HemW is annotated asa putative radical S-adenosylmethionine (SAM) enzymeand belongs to the HemN-like subfamily, but its biochemical propertiesremain unclear. Here, we report on the first experimental characterizationof M. catarrhalis HemW (McHemW). Our bioinformatic analysis confirmed its evolutionary relationshipwith the putative heme-binding radical SAM enzyme HemW in Escherichia coli. We experimentally demonstratedthat McHemW contains a catalytically active [4Fe-4S]cluster and binds heme through biochemical assays and spectroscopy.Using hydrogen–deuterium exchange mass spectrometry, we demonstrated,for the first time, that the heme-binding site resides within theC-terminal auxiliary domain unique to HemW. These findings providemechanistic insight into the molecular basis of heme recognition in McHemW and establish a foundation for understanding itsrole in the pathogenicity of M. catarrhalis under iron-limited conditions.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 4","pages":"468–483"},"PeriodicalIF":3.5,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structure-Guided Optimization of CHI3L1 Modulators Reveals G721–0377 as a Lead Compound for Restoring Astrocyte Function in Alzheimer’s Disease 结构导向优化CHI3L1调节剂揭示G721-0377是恢复阿尔茨海默病星形细胞功能的先导化合物

IF 3.5

ACS Bio & Med Chem Au Pub Date : 2026-08-19 Epub Date: 2026-04-28 DOI: 10.1021/acsbiomedchemau.5c00279

Baljit Kaur, Hossam Nada, Longfei Zhang, Moustafa Gabr

{"title":"Structure-Guided Optimization of CHI3L1 Modulators Reveals G721–0377 as a Lead Compound for Restoring Astrocyte Function in Alzheimer’s Disease","authors":"Baljit Kaur, Hossam Nada, Longfei Zhang, Moustafa Gabr","doi":"10.1021/acsbiomedchemau.5c00279","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.5c00279","url":null,"abstract":"Alzheimer’s disease (AD) involves astrocytic dysfunctioncharacterized by impaired lysosomal activity, defective amyloid clearance,and neuroinflammation, processes strongly regulated by the inflammatoryeffector CHI3L1. G721–0282, a reported CHI3L1-bindingsmall molecule with demonstrated modulation of downstream signalingpathways including MAPK and STAT3, provides a validated chemical startingpoint for targeting CHI3L1-driven astrocytic pathology in AD, butit exhibits suboptimal potency and drug-like properties that limitits translational potential. We therefore performed a virtual screeningof commercially available analogues of G721–0282 to enable structure-guided optimization, generating a detailed structure–activitymap, and prioritizing 24 derivatives. Biophysical analyses identifiedcompound G721–0377 as the most promising candidate,with optimized substitutions resulting in enhanced CHI3L1-bindingaffinity (Kd = 45 μM), representinga ∼3-5-fold improvement over related analogs (Kd = 65–236 μM). Compound G721–0377 also exhibited favorable physicochemicaland pharmacokinetic properties, including improved solubility, balancedpermeability, reduced microsomal clearance, and an enhanced cardiacsafety margin. Given their micromolar potency, all functional studieswere conducted in vitro. Functionally, G721–0377 uniquely reversed CHI3L1-induced astrocytic dysfunction, restoringamyloid uptake, lysosomal proteolysis and acidification, suppressingCHI3L1 and IL-6 secretion, and inhibiting NF-κB activation tolevels comparable to a neutralizing anti-CHI3L1 antibody. Collectively,these findings establish G721–0377 as a promisingearly stage lead compound with improved affinity, safety, and robustfunctional efficacy, supporting its further development as a disease-modifyingtherapeutic for AD.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 4","pages":"329–341"},"PeriodicalIF":3.5,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Modular Inhibitor Approach to Map the Catalytic Trajectory of an Iterative Siderophore Synthetase, DesD 模块化抑制剂方法绘制迭代铁载体合成酶（DesD）催化轨迹

IF 3.5

ACS Bio & Med Chem Au Pub Date : 2026-08-19 Epub Date: 2026-07-09 DOI: 10.1021/acsbiomedchemau.6c00078

Collin E. Merrick, Ketan D. Patel, Parismita Kalita, Nicole Gulati, Andrew M. Gulick, Timothy A. Wencewicz

{"title":"Modular Inhibitor Approach to Map the Catalytic Trajectory of an Iterative Siderophore Synthetase, DesD","authors":"Collin E. Merrick, Ketan D. Patel, Parismita Kalita, Nicole Gulati, Andrew M. Gulick, Timothy A. Wencewicz","doi":"10.1021/acsbiomedchemau.6c00078","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.6c00078","url":null,"abstract":"Under iron limitingconditions, bacteria biosynthesizeand secretesmall molecule iron chelators, siderophores, to scavenge this essentialmetal. Siderophores are biosynthesized by nonribosomal peptide synthetases(NRPS) or NRPS independent siderophore (NIS) synthetases, the latterof which are significantly less studied. Streptomyces spp. utilizes an iterative NIS synthetase, DesD, to produce desferrioxaminetype siderophores through dimerization, trimerization, and (in somecases) macrocyclization of monomers such as N1-hydroxy-N1-succinyl cadaverine(HSC) and N1-hydroxy-N1-acetyl cadaverine (HAC). Prior work has utilized anacyl-sulfamoyl adenosine (AMS) inhibitor of monomeric HSC (HSC-AMS)to interrogate the initial adenylation reaction of HSC. However, muchis still unknown about how the enzyme active site accommodates substratesof varying sizes during further oligomerization reactions. To answerthis question, AMS analogs of the monomer (HSC-AMS), dimer (HSC-HSC-AMS),and trimer (HSC-HSC-HSC-AMS) were chemically synthesized. Biochemicalresults from in vitro DesD reactions, IC50 assays, and isothermal titration calorimetry along with structuralstudies conducted via cocrystallization inform an updated mechanisticmodel for the iterative DesD catalytic cycle. The acyl adenylate motifin the growing substrate chain drives tight binding in the enzymeactive site while the N-terminal HSC units dynamically sample conformationsen route to terminating macrocyclization of the HSC-HSC-HSC trimer.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 4","pages":"393–409"},"PeriodicalIF":3.5,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting FLT3 in Acute Myeloid Leukemia: Structural Insights and Key Challenges 靶向FLT3治疗急性髓性白血病：结构见解和关键挑战

IF 3.5

ACS Bio & Med Chem Au Pub Date : 2026-08-19 Epub Date: 2026-04-20 DOI: 10.1021/acsbiomedchemau.6c00021

Michele Rodrigues da Silva, Lídia Moreira Lima, Maria Letícia de Castro Barbosa

{"title":"Targeting FLT3 in Acute Myeloid Leukemia: Structural Insights and Key Challenges","authors":"Michele Rodrigues da Silva, Lídia Moreira Lima, Maria Letícia de Castro Barbosa","doi":"10.1021/acsbiomedchemau.6c00021","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.6c00021","url":null,"abstract":"Mutations in FLT3 (FMS-like tyrosine kinase 3) are directlyrelatedto the development of acute myeloid leukemia (AML), contributing tothe dysregulated proliferation and survival of malignant myeloid cells.FLT3 inhibitors (FLT3i), such as gilteritinib and quizartinib, havedemonstrated relevant clinical benefits, including symptom reliefand increased overall survival in patients with AML. However, theduration of response to FLT3i remains limited due to the emergenceof resistance. In this scenario, the development of targeted therapieshas emerged as a promising strategy to overcome these limitations,aiming to address the restrictions observed in the previous generation.These approaches range from the combination of FLT3i with other antileukemicagents to the use of multitarget inhibitors capable of simultaneouslymodulating FLT3 and other relevant molecular targets, as well as thedevelopment of next-generation inhibitors that are more selectiveand capable of maintaining activity against secondary mutations, suchas the gatekeeper mutation (F691L), which confers resistance to clinicallyavailable drugs. This review article addresses the therapeutic relevanceof FLT3i in AML and provides an overview of the binding modes of representativeFLT3 inhibitors. Structural and conformational aspects involved inthe interaction with this target, with emphasis on the ATP-bindingsite, as well as the impact of resistance-associated mutations, arediscussed. In addition, this work seeks to correlate the binding modesdescribed in the literature with experimental activity data.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 4","pages":"305–322"},"PeriodicalIF":3.5,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural Remodeling of Mitochondrial Membranes in Cancerous Colon Cells: Insights from Neutron Scattering and Lipidomics 结肠癌细胞线粒体膜的结构重塑：中子散射和脂质组学的见解

IF 3.5

ACS Bio & Med Chem Au Pub Date : 2026-08-19 Epub Date: 2026-07-22 DOI: 10.1021/acsbiomedchemau.6c00106

Stuart R. Castillo, Natalie M. Robinson, Maksymilian Dziura, Omotayo Gbadamosi, Dominik Dziura, Isabelle J. Dib, Éilís C. Bragginton, Emma Buzzard, Karen M. Davies, Najet Mahmoudi, Piotr A. Zolnierczuk, Elizabeth G. Kelley, Drew Marquardt

{"title":"Structural Remodeling of Mitochondrial Membranes in Cancerous Colon Cells: Insights from Neutron Scattering and Lipidomics","authors":"Stuart R. Castillo, Natalie M. Robinson, Maksymilian Dziura, Omotayo Gbadamosi, Dominik Dziura, Isabelle J. Dib, Éilís C. Bragginton, Emma Buzzard, Karen M. Davies, Najet Mahmoudi, Piotr A. Zolnierczuk, Elizabeth G. Kelley, Drew Marquardt","doi":"10.1021/acsbiomedchemau.6c00106","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.6c00106","url":null,"abstract":"Herein, we show compellingevidence of structural remodeling inmitochondrial membranes of cancerous colon cells when compared totheir noncancerous counterparts. The physical characteristics of cancerousand noncancerous mitochondria were systematically investigated usingsmall-angle neutron scattering (SANS), cryogenic electron tomography(cryo-ET), neutron spin–echo (NSE) spectroscopy, and high-throughputlipidomics. Our results exhibit evidence of both mechanical softeningof the mitochondrial membrane, as seen by NSE, and ultrastructurerearrangements of the inner mitochondrial membranes, as seen by SANSand cryo-ET, in cancerous cells. These differences in properties seemto be correlated with changes in the lipidome, suggesting the changesare due to the limited number of lipid classes immediately availableduring the rapid proliferation of cancerous cells. Finally, we highlighta mechanism by which pancratistatin (PST), a natural anticancer therapeuticcandidate, may selectively induce apoptosis by altering the mechanicalproperties and ultrastructure of cancerous mitochondria while sparingnoncancerous mitochondria. Discovery of these structural anomalieswill lead to improvements in diagnostics, therapeutic development,and the advancement of targeted approaches for traditionally complexcancers which evade our current treatments.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 4","pages":"443–455"},"PeriodicalIF":3.5,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Molecular Insights on the Assembling of ParB1 and ParB1-parS1 Partition Complex ParB1和ParB1- pars1分割复合物组装的分子研究

IF 3.5

ACS Bio & Med Chem Au Pub Date : 2026-08-19 Epub Date: 2026-06-19 DOI: 10.1021/acsbiomedchemau.5c00284

Anu Anu, Sneh Lata, Barnali N. Chaudhuri

{"title":"Molecular Insights on the Assembling of ParB1 and ParB1-parS1 Partition Complex","authors":"Anu Anu, Sneh Lata, Barnali N. Chaudhuri","doi":"10.1021/acsbiomedchemau.5c00284","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.5c00284","url":null,"abstract":"ParB, which is a condensate-forming DNA clamp and a CTPswitch,is a key member of the bacterial chromosome segregation apparatus.Molecular features that govern the assembly of ParB for partitionassembly condensate formation that leads to DNA segregation are sparselyunderstood. We report that ParB1 from the multipartite bacteria Vibrio cholerae is a CTPase. The AI-predicted structuralmodel of the ParB1-parS1 nucleoprotein complex consistentwith small-angle X-ray scattering revealed how parS1 loading primes ParB1 for sliding, with the formation of a lumenfor housing the sliding DNA. The CTPase domains in this dimeric ParB1-parS1 structure are accessible for the formation of higher-orderassemblies. Furthermore, we showed that a truncated N-terminal segmentof ParB1 containing the CTPase domain undergoes concentration-dependentoligomerization. A flexible linker joining this oligomerization-proneN-terminal segment and the C-terminal dimerization domain appearsto intrinsically restrain the self-association of full-length ParB1.Our results suggest that the oligomerization propensity of the N-terminalsegment of ParB1 is a key factor for higher-order partition assemblyformation.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 4","pages":"342–352"},"PeriodicalIF":3.5,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mechanistic Insights into β-1,6-Branch Recognition and Orientation-Selective Hydrolysis by Endo-β-1,3-Glucanase Using Synthetic β-Glucan Probes 利用合成β-葡聚糖探针研究β-1,6支识别和Endo-β-1,3-葡聚糖酶定向选择性水解的机理

IF 3.5

ACS Bio & Med Chem Au Pub Date : 2026-08-19 Epub Date: 2026-07-02 DOI: 10.1021/acsbiomedchemau.6c00086

Atsushi Miyagawa, Takahiro Yamaguchi, Masayuki Oda, Hatsuo Yamamura

{"title":"Mechanistic Insights into β-1,6-Branch Recognition and Orientation-Selective Hydrolysis by Endo-β-1,3-Glucanase Using Synthetic β-Glucan Probes","authors":"Atsushi Miyagawa, Takahiro Yamaguchi, Masayuki Oda, Hatsuo Yamamura","doi":"10.1021/acsbiomedchemau.6c00086","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.6c00086","url":null,"abstract":"Understanding how glycoside hydrolases structurally heterogeneouspolysaccharides remains a central challenge due to the limited availabilityof well-defined substrates. Here, we establish a chemically defined,probe-based platform to systematically dissect the hydrolytic specificityof an endo-β-1,3-glucanase using a systematicallydesigned library of branched β-1,3-glucan oligosaccharides withprecisely controlled branch position and length. Synthetic accessto these glycans enabled their conversion into fluorescent probesfor sensitive, site-specific analysis of enzymatic cleavage. Our resultsrevealed that β-1,6-linked branching acts as a key structuraldeterminant governing both cleavage efficiency and positional selectivityin a branched length-dependent manner. While monosaccharide branchesare broadly accommodated, disaccharide branches introduce steric constraintsthat significantly suppress hydrolysis. Notably, analysis using anextended octasaccharide substrate uncovered a dominant cleavage atthe central β-1,3-glycosidic bond, allowing refinement and expansionof the enzyme subsite model beyond that accessible with shorter substrates.Collectively, these findings define branch architecture as a criticalregulator of substrate orientation and cleavage-site selection, andestablish chemically defined glycan libraries as a generalizable platformfor mechanistic interrogation of glycoside hydrolases.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 4","pages":"423–431"},"PeriodicalIF":3.5,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Fine-Tuning hIAPP Amyloidogenesis: Probing Molecular Mechanisms via Fluorinated Core Substitutions 微调hIAPP淀粉样蛋白发生：通过氟化核取代探测分子机制

IF 3.5

ACS Bio & Med Chem Au Pub Date : 2026-08-19 Epub Date: 2026-05-05 DOI: 10.1021/acsbiomedchemau.6c00061

Artem Pavlov, Hossein Batebi, Nicklas Österlund, Kevin Pagel, Boris Schade, Mario Schubert, Roland R. Netz, Beate Koksch

{"title":"Fine-Tuning hIAPP Amyloidogenesis: Probing Molecular Mechanisms via Fluorinated Core Substitutions","authors":"Artem Pavlov, Hossein Batebi, Nicklas Österlund, Kevin Pagel, Boris Schade, Mario Schubert, Roland R. Netz, Beate Koksch","doi":"10.1021/acsbiomedchemau.6c00061","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.6c00061","url":null,"abstract":"Aggregation of human islet amyloid polypeptide (hIAPP,amylin)into amyloid fibrils is a hallmark of β-cell dysfunction intype 2 diabetes, yet the molecular determinants governing its aggregationpathways remain incompletely understood. Here, we investigate howsystematic fluorination of Phe23─a key aromatic residue withinthe amyloidogenic core─modulates intra- and intermolecularinteractions and thereby probes hIAPP self-assembly under physiologicallyrelevant acidic and neutral pH conditions. Using a combination ofThioflavin T kinetics, scaling-exponent analysis, pyrene fluorescence,ion mobility–mass spectrometry, circular dichroism, 19F NMR spectroscopy, and molecular dynamics simulations, we show thatfluorination of Phe23 reshapes aggregation behavior in a highly nonadditivemanner. While wild-type and minimally fluorinated variants, at neutralpH, follow the surface-catalyzed secondary nucleation mechanism discussedwell in the literature, higher degrees of fluorination progressivelyreduce monomer dependence and give rise to pronounced concentration-dependent,self-inhibiting aggregation behavior. Under acidic conditions, protonationof His18 leads to a divergent concentration dependence, with reducedmonomer dependence for wild-type and minimally fluorinated peptidesand enhanced concentration sensitivity for tetra- and penta-fluorinatedvariants. These concentration dependencies reflect differences inthe conformational accessibility, flexibility, and oligomerizationefficiency required for productive fibril formation under each pHcondition. Together, these results identify Phe23 as a molecular switchthat couples local interactions to global aggregation pathways anddemonstrate how subtle chemical and environmental perturbations canmodulate the productivity of hIAPP fibril formation.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 4","pages":"381–392"},"PeriodicalIF":3.5,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ultratight Binding of a Capture Spiral Spider Silk Protein through Electrostatic Forces 通过静电力捕获螺旋蜘蛛丝蛋白的超紧密结合

IF 3.5

ACS Bio & Med Chem Au Pub Date : 2026-08-19 Epub Date: 2026-06-11 DOI: 10.1021/acsbiomedchemau.6c00054

Johanna Meyer, Hannes Neuweiler

{"title":"Ultratight Binding of a Capture Spiral Spider Silk Protein through Electrostatic Forces","authors":"Johanna Meyer, Hannes Neuweiler","doi":"10.1021/acsbiomedchemau.6c00054","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.6c00054","url":null,"abstract":"Web spiders assemblesoluble silk proteins, so-called spidroins,into fibers with extraordinary toughness. The spidroin N-terminaldomains (NTDs) are highly conserved self-assembly modules that dimerizeinduced by chemical stimuli within the spinning duct. Spidroins fromthe flagelliform spinning gland form tough and elastic capture spiralsilk. Their NTDs exhibit an unusual content of charged amino acidside chains with an unknown function. Here, we engineered a molecularexciton probe into a flagelliform spidroin NTD to detect the mechanismand strength of binding through kinetic fluorescence in combinationwith chemical denaturation experiments. Site-directed mutagenesisexperiments revealed that salt bridges formed by few additional sidechain charges tighten the dimer dramatically, reducing the equilibriumdissociation constant by five to six orders of magnitude. The centralhelix of the dimerization interface resembles a dipolar electrostaticstalk that, through cooperative effects within an antiparallel dimer,generates an equilibrium dissociation constant in the femtomolar range.The additional electrostatic forces acting between flagelliform spidroinNTDs are likely to contribute to the remarkable mechanical propertiesof capture spiral silk.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 4","pages":"368–380"},"PeriodicalIF":3.5,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Conjugated NOD1-Centered Dual Agonists Exhibit Modest In Vitro Immunomodulation but Potent In Vivo Adjuvanticity 以nod1为中心的偶联双激动剂在体外具有适度的免疫调节作用，但在体内具有强大的佐剂作用

IF 3.5

ACS Bio & Med Chem Au Pub Date : 2026-08-19 Epub Date: 2026-06-15 DOI: 10.1021/acsbiomedchemau.6c00080

Emiliano Paradiso, Špela Janež, Veronika Weiss, Ruža Frkanec, Žiga Jakopin

引用次数: 0