Protein Science最新文献_第3页

Exploring the sequence and structural determinants of the energy landscape from thermodynamically stable and kinetically trapped subtilisins: ISP1 and SbtE. 从热力学稳定和动力学捕获的枯草菌素ISP1和SbtE探索能量景观的序列和结构决定因素。

IF 5.2 3区生物学

Protein Science Pub Date : 2025-09-01 DOI: 10.1002/pro.70264

Miriam R Hood, Susan Marqusee

{"title":"Exploring the sequence and structural determinants of the energy landscape from thermodynamically stable and kinetically trapped subtilisins: ISP1 and SbtE.","authors":"Miriam R Hood, Susan Marqusee","doi":"10.1002/pro.70264","DOIUrl":"10.1002/pro.70264","url":null,"abstract":"A protein's energy landscape, all accessible conformations, their populations, and dynamics of interconversion, is encoded in its primary sequence. While how this sequence encodes a protein's native state is well understood, how it encodes the dynamics, such as the kinetic barriers for unfolding and refolding, is not. Here we have looked at two subtiliase homologs from Bacillus subtilis, Intracellular Subtilisin Protease 1 (ISP1) and Subtilisin E (SbtE), that are expected to have very different dynamics. ISP1, an intracellular protein, has a small pro-domain thought to act simply as a zymogen, whereas the extracellular SbtE has a large pro-domain required for folding. The stability and kinetics of the mature proteins have been previously characterized; here we compare their energy landscapes with and without the pro-domain, examining global and local energetics of the mature proteases and the effect of each pro-domain. We find that ISP1's pro-domain has limited impact on the energy landscape of the mature protein. For SbtE, the protein is thermodynamically unstable and kinetically trapped without the pro-domain. The pro-domains' effects on the flexibility of the core of the proteins are different: in the absence of its pro-domain, ISP1's core becomes more flexible, while SbtE's core becomes more rigid. ISP1 contains a conserved insertion, which points to a potential source for these differences. These homologs show how changes in the primary sequence can dramatically alter a protein's energy landscape and highlight the need for large-scale, high-throughput studies on the relationship between primary sequence and conformational dynamics.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 9","pages":"e70264"},"PeriodicalIF":5.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12359198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Computational structure prediction of lanthipeptides with NMR data reveals underappreciated peptide flexibility. 用核磁共振数据预测镧硫肽的计算结构揭示了被低估的肽的灵活性。

IF 5.2 3区生物学

Protein Science Pub Date : 2025-09-01 DOI: 10.1002/pro.70252

Claiborne W Tydings, Jens Meiler, Allison S Walker

{"title":"Computational structure prediction of lanthipeptides with NMR data reveals underappreciated peptide flexibility.","authors":"Claiborne W Tydings, Jens Meiler, Allison S Walker","doi":"10.1002/pro.70252","DOIUrl":"10.1002/pro.70252","url":null,"abstract":"Lanthipeptides are a class of thioether-containing ribosomally synthesized and post-translationally modified peptides, which often have antibiotic activity. As a potential starting point for therapeutics, interest in engineering lanthipeptides is growing. Our inability to computationally model and design lanthipeptides in molecular modeling and design software such as Rosetta limits our ability to rationally design lanthipeptides for drug discovery campaigns. We propose that implementing support for the lanthionine rings and dehydrated amino acids found in lanthipeptides will enable accurate lanthipeptide modeling with Rosetta. We find that when compared to the ensembles of lanthipeptides with NMR-determined structures in the PDB, lanthipeptide ensembles generated with Rosetta have similar experimental agreement, lower Rosetta energy scores, and greater flexibility. Our use of ensemble-averaged NOE distances instead of requiring individual structures to satisfy all NOE restraints was key for revealing the flexibility of these peptides. Our Rosetta lanthipeptide ensembles show increased flexibility in non-cyclized peptide regions as well as increased lanthionine ring flexibility when internal hydrogen bonds are absent and glycine residues are present. Support for lanthipeptides in Rosetta enables the design and modeling of lanthipeptides in Rosetta for therapeutic development.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 9","pages":"e70252"},"PeriodicalIF":5.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12359204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural insight into the substrate binding of the AMT complex via an inhibitor-trapped state. 通过抑制剂捕获状态深入了解AMT复合物的底物结合结构。

IF 5.2 3区生物学

Protein Science Pub Date : 2025-09-01 DOI: 10.1002/pro.70265

Zengyu Shao, Sol Yoon, Jiuwei Lu, Pranav Athavale, Yifan Liu, Jikui Song

{"title":"Structural insight into the substrate binding of the AMT complex via an inhibitor-trapped state.","authors":"Zengyu Shao, Sol Yoon, Jiuwei Lu, Pranav Athavale, Yifan Liu, Jikui Song","doi":"10.1002/pro.70265","DOIUrl":"10.1002/pro.70265","url":null,"abstract":"N6-adenine (6mA) DNA methylation plays an important role in gene regulation and genome stability. The 6mA methylation in Tetrahymena thermophila is mainly mediated by the AMT complex, comprised of the AMT1, AMT7, AMTP1, and AMTP2 subunits. To date, how this complex assembles on the DNA substrate remains elusive. Here we report the structure of the AMT complex bound to the OCR protein from bacteriophage T7, mimicking the AMT-DNA encounter complex. The AMT1-AMT7 heterodimer approaches OCR from one side, while the AMTP1 N-terminal domain, assuming a homeodomain fold, binds to OCR from the other side, resulting in a saddle-shaped architecture reminiscent of what was observed for prokaryotic 6mA writers. Mutation of the AMT1, AMT7, and AMTP1 residues on the OCR-contact points led to impaired DNA methylation activity to various extents, supporting a role for these residues in DNA binding. Furthermore, structural comparison of the AMT1-AMT7 subunits with the evolutionarily related METTL3-METTL14 and AMT1-AMT6 complexes reveals sequence conservation and divergence in the region corresponding to the OCR-binding site, shedding light on the substrate binding of the latter two complexes. Together, this study supports a model in which the AMT complex undergoes a substrate binding-induced open-to-closed conformational transition, with implications in its substrate binding and processive 6mA methylation.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 9","pages":"e70265"},"PeriodicalIF":5.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144856120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Using extension-based mRNA display to design antibody-like proteinogenic peptides for human PD-L1. 利用基于延伸的mRNA展示设计人PD-L1抗体样蛋白生成肽。

IF 5.2 3区生物学

Protein Science Pub Date : 2025-09-01 DOI: 10.1002/pro.70268

Justin N Ong, Brian J Grindel, Scott A Rankin, Sarah H Naylon, Anupallavi Srinivasamani, Guillaume J Trusz, Xiaowen Liang, Md Nasir Uddin, Lauren Fuller, Michael Curran, Stephane P Roche, Terry T Takahashi, Richard W Roberts, Steven W Millward

{"title":"Using extension-based mRNA display to design antibody-like proteinogenic peptides for human PD-L1.","authors":"Justin N Ong, Brian J Grindel, Scott A Rankin, Sarah H Naylon, Anupallavi Srinivasamani, Guillaume J Trusz, Xiaowen Liang, Md Nasir Uddin, Lauren Fuller, Michael Curran, Stephane P Roche, Terry T Takahashi, Richard W Roberts, Steven W Millward","doi":"10.1002/pro.70268","DOIUrl":"https://doi.org/10.1002/pro.70268","url":null,"abstract":"Many peptide drugs rely on nonproteinogenic amino acids and chemical modifications for improved activity and proteolytic stability. However, these features also make drug production expensive and challenging to scale. Here, we engineered small, linear, proteinogenic peptides that bind human programmed death-ligand 1 (hPD-L1) with high affinity and stability using mRNA display affinity maturation. The resulting peptides, SPAM2 and SPAM3, have antibody-like affinities for hPD-L1 (dissociation constants between ~250 and 300 pM) and are selective for hPD-L1. Both SPAM2 and SPAM3 compete with hPD-L1 ligands known to interact with the programmed cell death protein 1 site and are stable in human serum. SPAM3 bound human glioma D423 cells with high affinity in flow cytometry experiments comparable to that of a clinical therapeutic antibody. These results support the use of affinity maturation selections to dramatically enhance the biophysical properties of linear, proteinogenic peptides for translational applications.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 9","pages":"e70268"},"PeriodicalIF":5.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12376068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144966367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

AlphaFold modeling uncovers global structural features of class I and class II fungal hydrophobins. AlphaFold模型揭示了I类和II类真菌疏水酶的整体结构特征。

IF 5.2 3区生物学

Protein Science Pub Date : 2025-09-01 DOI: 10.1002/pro.70279

Li-Yen Yang, Daniel J Hicks, Paul S Russo, Andrew C McShan

{"title":"AlphaFold modeling uncovers global structural features of class I and class II fungal hydrophobins.","authors":"Li-Yen Yang, Daniel J Hicks, Paul S Russo, Andrew C McShan","doi":"10.1002/pro.70279","DOIUrl":"https://doi.org/10.1002/pro.70279","url":null,"abstract":"Hydrophobins are a family of small fungal proteins that self-assemble at hydrophobic-hydrophilic interfaces. Hydrophobins not only play crucial roles in filamentous fungal growth and development but also have attracted substantial attention due to their unique material properties. Structural characterization of class I and class II hydrophobins to date has been limited to a handful of proteins. While machine-learning-based structure prediction methods have the potential to exponentially expand our ability to define global structure-function relationships of biomolecules, they have not yet been extensively applied to hydrophobins. Here, we apply a suite of bioinformatics tools including Rosetta, AlphaFold, FoldMason, and Foldseek toward analysis, modeling, classification, and global comparison of class I and class II hydrophobins. We first probe the structural and energetic features of experimental class I and class II structures available in the Protein Data Bank. Using previously solved X-ray and NMR structures, we benchmark the ability of AlphaFold to predict class I and class II hydrophobin folds. We explore the physicochemical properties of more than 7,000 class I and class II hydrophobins in the UniProt database. Then, using AlphaFold models, we classify the structural universe of all known class I and class II hydrophobins into six distinct clades. We also uncover putative non-canonical features of hydrophobins, including extended N-terminal tails, five disulfide bonds, polyhydrophobins, and non-hydrophobin proteins containing hydrophobin-like folds. Finally, we examine the ability of AlphaFold and Chai-1 to model hydrophobin membrane binding, conformational changes, and self-assembly of class I rodlets and class II meshes. Together, our results highlight that AlphaFold not only accurately models and enables the global comparison of features within the hydrophobin protein family but also uncovers new properties that can be further evaluated with experimentation.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 9","pages":"e70279"},"PeriodicalIF":5.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12375992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144966524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Controlling gene expression through five zinc finger domains of ZNF18. 通过ZNF18的5个锌指结构域调控基因表达。

IF 5.2 3区生物学

Protein Science Pub Date : 2025-09-01 DOI: 10.1002/pro.70278

Soyeon Park, Yunha Hwang, Ki Seong Eom, Jin Sung Cheong, Seung Jae Lee

{"title":"Controlling gene expression through five zinc finger domains of ZNF18.","authors":"Soyeon Park, Yunha Hwang, Ki Seong Eom, Jin Sung Cheong, Seung Jae Lee","doi":"10.1002/pro.70278","DOIUrl":"10.1002/pro.70278","url":null,"abstract":"Zinc finger (ZF) proteins are the most abundant transcription factors in vertebrates, and they regulate gene expression through interactions with cis-acting elements. ZF domains selectively recognize specific sequences to accelerate or repress target genes. Zinc finger protein 18 (ZNF18) contains five CX2CX12HX3H-type ZFs at the C-terminus, which are expressed in the brain and other organs of the biological system. Bioinformatic study proposed that cyclin-dependent kinase 1 (CDK1) is in the signaling cascade of ZNF18; although experimental evidence has not yet been reported. In this study, we expressed and purified ZNF18(ZF1-5), five ZF domains from ZNF18, and investigated metal binding specificity and promoter interactions. ZNF18(ZF1-5) has specific coordination to Zn2+ (Kd ≤ 18 nM) compared with other xenobiotic metal ions, including Co2+, Fe2+, and Fe3+, with 98.5% of reduced ZF domains after purification. This significantly active ZF can be one of the major reasons for tight coordination affinity. CDK1 rescued the arrested cell cycle induced by DNA damage, resulting in tumorigenesis. Zn2+-ZNF18(ZF1-5) specifically binds to cis-acting elements of cdk1 (Kd = 4.63 ± 0.07 nM), mediated by a cell cycle-dependent element (cde, 5'-CGCGG) and a cell cycle gene homology region (chr, 5'-TTGAA). The ZNF18 superfamily was expressed in the brain for the regulation of neuronal development and cell differentiation. Zn2+-ZNF18(ZF1-5) interacted with promoters in the insulin response sequence (IRS) for inhibition of dopamine secretion and cis-acting element of brain-2 (BRN2), which controlled astrocyte and cancer development. These results provide the first evidence that ZNF18(ZF1-5) regulates the cell cycle and neuronal development through transcriptional regulation.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 9","pages":"e70278"},"PeriodicalIF":5.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12359201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Temperature induces a shift from insulin dihexamer to hexamer in collective dynamics. 温度诱导胰岛素二聚体向六聚体的转变。

IF 5.2 3区生物学

Protein Science Pub Date : 2025-09-01 DOI: 10.1002/pro.70245

Esra Ayan

{"title":"Temperature induces a shift from insulin dihexamer to hexamer in collective dynamics.","authors":"Esra Ayan","doi":"10.1002/pro.70245","DOIUrl":"10.1002/pro.70245","url":null,"abstract":"Structures based on x-ray diffraction data collected at 2.3, 2.88, and 2.95 Å resolutions have been determined for long-acting dihexamer insulin at three different temperatures, ranging from 100 to 300 K. It has been observed that the unit-cell parameters of the insulin crystal at 100 K change at 200 K. This change is likely due to the subtle repacking of the rhombohedral insulin crystal and the loss of noncovalent interactions involving myristic acid, which binds two hexamers. Computational analyses indicate that allosteric residues and fatty acid-binding residues of insulin hexamers exhibit reduced collective dynamics and inter-residue coupling, possibly resulting from increased structural fluctuations due to elevated thermal vibrations. This transition has been observed at a characteristic temperature of 200 K, potentially highlighting underlying alterations in the dynamic structure of the fatty acid-solvent interface in the dimer of hexamers. Combined with computational analyses, these findings provide key insights into thermal stability mechanisms, which are crucial for developing thermostable insulin formulations in industrial applications.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 9","pages":"e70245"},"PeriodicalIF":5.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144856189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A β-1,2-glucan-associated glycoside hydrolase family 1 β-glucosidase from Streptomyces griseus. 来自灰色链霉菌的β-1,2-葡聚糖相关糖苷水解酶家族1 β-葡萄糖苷酶。

IF 5.2 3区生物学

Protein Science Pub Date : 2025-09-01 DOI: 10.1002/pro.70255

Haruto Kumakura, Sei Motouchi, Kaito Kobayashi, Miyu Inoue, Natsuki Kariuda, Hiroyuki Nakai, Masahiro Nakajima

{"title":"A β-1,2-glucan-associated glycoside hydrolase family 1 β-glucosidase from Streptomyces griseus.","authors":"Haruto Kumakura, Sei Motouchi, Kaito Kobayashi, Miyu Inoue, Natsuki Kariuda, Hiroyuki Nakai, Masahiro Nakajima","doi":"10.1002/pro.70255","DOIUrl":"https://doi.org/10.1002/pro.70255","url":null,"abstract":"β-Glucosidases, major enzymes that release glucose from various natural compounds, are phylogenetically classified into glycoside hydrolase (GH) families. GH1 is the largest of these families. No β-1,2-glucan-associated GH1 enzyme has been found, even though β-1,2-glucans are natural carbohydrates that are important for interaction between organisms and environmental adaptation. In this study, functional and structural analyses of a GH1 enzyme from Streptomyces griseus (SGR_2426 protein) were performed. SGR_2426 showed the highest hydrolytic activity toward p-nitrophenyl β-glucopyranoside among p-nitrophenyl sugars. This enzyme showed hydrolytic activity toward β-1,2-glucooligosaccharides specifically among β-linked glucooligosaccharides. A structure of the enzyme in complex with sophorose (β-1,2-glucodisaccharide) was obtained as a Michaelis complex. The six-membered ring of the glucose unit at the reducing end of sophorose is positioned in a hydrophobic environment between Trp291 and Met171, while only residue Gln229 forms a hydrogen bond directly. Trp291 and Gln229 are proposed as candidates for the residues important for substrate specificity based on comparison with structurally characterized GH1 homologs. Mutational analysis of Trp291 and Gln229 suggested that Trp291 is important for substrate recognition but not for substrate specificity and that Gln229 is involved in substrate specificity. SGR_2426 is the first identified β-1,2-glucan-associated β-glucosidase in the GH1 family.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 9","pages":"e70255"},"PeriodicalIF":5.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12369401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144966461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unveiling the molecular mechanism of G_i protein biased activation at mGlu₂-mGlu₄ heterodimers through Gaussian accelerated molecular dynamics simulations. 通过高斯加速分子动力学模拟揭示mGlu2-mGlu4异源二聚体中Gi蛋白偏态活化的分子机制。

IF 5.2 3区生物学

Protein Science Pub Date : 2025-09-01 DOI: 10.1002/pro.70277

Baoyu He, Longfei Mao, Xiaojie Jin, Hongliang Duan, Jingjing Guo

{"title":"Unveiling the molecular mechanism of Gi protein biased activation at mGlu2-mGlu4 heterodimers through Gaussian accelerated molecular dynamics simulations.","authors":"Baoyu He, Longfei Mao, Xiaojie Jin, Hongliang Duan, Jingjing Guo","doi":"10.1002/pro.70277","DOIUrl":"10.1002/pro.70277","url":null,"abstract":"Metabotropic glutamate (mGlu) receptors play a crucial role in synaptic transmission through homodimeric or heterodimeric assemblies. Despite their dimeric nature, only one subunit within the mGlu dimer engages with G proteins during activation, and the biased activation can be further controlled by allosteric modulators. Considering the related molecular mechanisms remain elusive, we employed Gaussian accelerated molecular dynamics (GaMD) simulations to investigate the regulated mechanisms in mGlu2-mGlu4 heterodimers. Our results demonstrate that the Gi protein exhibits a higher binding affinity for mGlu4 compared to mGlu2 within the mGlu2-mGlu4 heterodimer. Meanwhile, when the positive allosteric modulator (PAM) binds to Gi-coupled subunits-whether mGlu2 or mGlu4-it can enhance the binding affinity between the Gi protein and the subunits of the mGlu2-mGlu4 heterodimer. However, if the PAM binds to mGlu2 while the Gi protein is coupled to mGlu4, the binding affinity may be reduced. Additionally, our results highlight the crucial role of the ICL2 region and the perturbation of the residue-residue coupling network involved in the regulatory pathways in mediating the PAM-induced modulation of Gi protein preference. In conclusion, these findings provide novel insights into the molecular mechanism underpinning the Gi protein's preference for mGlu4 within the mGlu2-mGlu4 heterodimers and the regulatory influence of PAM on Gi protein binding, advancing our understanding of their functional mechanisms.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 9","pages":"e70277"},"PeriodicalIF":5.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12359205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibitor-induced dimerization mediates lufotrelvir resistance in mutants of SARS-CoV-2 3C-like protease. 抑制剂诱导的二聚化介导sars - cov - 23c样蛋白酶突变体对氟替瑞韦的耐药性

IF 5.2 3区生物学

Protein Science Pub Date : 2025-09-01 DOI: 10.1002/pro.70275

Guanyu Wang, Felipe Venegas, Andres Rueda, Osvaldo Yañez, Manuel I Osorio, Sibei Qin, José Manuel Pérez-Donoso, Christopher J Thibodeaux, Nicolas Moitessier, Anthony K Mittermaier

{"title":"Inhibitor-induced dimerization mediates lufotrelvir resistance in mutants of SARS-CoV-2 3C-like protease.","authors":"Guanyu Wang, Felipe Venegas, Andres Rueda, Osvaldo Yañez, Manuel I Osorio, Sibei Qin, José Manuel Pérez-Donoso, Christopher J Thibodeaux, Nicolas Moitessier, Anthony K Mittermaier","doi":"10.1002/pro.70275","DOIUrl":"https://doi.org/10.1002/pro.70275","url":null,"abstract":"The emergence of SARS-CoV-2 and other lethal coronaviruses has prompted extensive research into targeted antiviral treatments, particularly focusing on the viral 3C-like protease (3CLpro) due to its essential role for viral replication. However, the rise of drug resistance mutations poses threats to public health and underscores the need to predict resistance mutations and understand the mechanism of how these mutations confer resistance. The binding of inhibitor to 3CLpro drives it from the monomeric to the active dimeric form, which can counterintuitively lead to enzyme activation rather than inhibition. Furthermore, we find this allosteric coupling between binding and dimerization is sensitive to mutation, leading to a new mechanism for drug resistance. Understanding the relationship between inhibitor binding and dimerization is important for resistant strain surveillance and development of robust antivirals. Herein, we present a systematic study of drug resistance mediated by inhibitor-induced dimerization of 3CLpro.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 9","pages":"e70275"},"PeriodicalIF":5.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12375981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144966468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0