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The Study of Carbamoyl Phosphate Synthetase 1 Deficiency Sheds Light on the Mechanism for Switching On/Off the Urea Cycle

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Journal of Genetics and Genomics 2015年第5期42卷 249-260页

作者： Carmen Díez-Fernández José Gallego Johannes H?berle Javier Cervera Vicente Rubio Institute for Biomedicine of Valencia of the Spanish Research Council Medical School of the Catholic University of Valencia University Children's Hospital Zurich and Children's Research Center Centre for Biomedical Networking Research on Rare Diseases of the Carlos Ⅲ Health Institute

Carbamoyl phosphate synthetase i （CPS1） deficiency （CPS1D） is an inborn error of the urea cycle having autosomal （2q34） recessive inheritance that can cause hyperammonemia and neonatal death or mental retardation. We analyzed the effects on CPS1 activity, kinetic parameters and enzyme stability of missense mutations reported in patients with CPS1 deficiency that map in the 20-kDa C-terminal domain of the enzyme. This domain turns on or off the enzyme depending on whether the essential allosteric activator of CPS 1, N-acetyl- L-glutamate （NAG）, is bound or is not bound to it. To carry out the present studies, we exploited a novel system that allows the expression in vitro and the purification of human CPS1, thus permitting site-directed mutagenesis. These studies have clarified disease causation by individual mutations, identifying functionally important residues, and revealing that a number of mutations decrease the affinity of the enzyme for NAG. Patients with NAG affinity-decreasing mutations might benefit from NAG site saturation therapy with N-carbamyl-L- glutamate （a registered drug, the analog of NAG）. Our results, together with additional present and prior site-directed mutagenesis data for other residues mapping in this domain, suggest an NAG-triggered conformational change in the 134-~4 loop of the C-terminal domain of this enzyme. This change might be an early event in the NAG activation process. Molecular dynamics simulations that were restrained according to the observed effects of the mutations are consistent with this hypothesis, providing further backing for this structurally plausible signaling mechanism by which NAG could trigger urea cycle activation via CPS1.

关键词： Urea cycle diseases Inborn errors Hyperammonemia Site-directed mutagenesis Restrained molecular dynamics allosteric regulation Carbamoyl phosphate synthetase 1 Enzyme

Steroid hormone receptors and prostate cancer： role of structural dynamics in therapeutic targeting

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Asian Journal of Andrology 2016年第5期18卷 682-686页

作者： Raj Kumar Department of Basic Sciences The Commonwealth Medical College Scranton PA USA.

Steroid hormone receptors （SHRs） act in cell type- and gene-specific manner through interactions with coregulatory proteins to regulate numerous physiological and pathological processes at the level of gene regulation. Binding of steroid receptor modulator （SRM） ligand leads to allosteric changes in SHR to exert positive or negative effects on the expression of target genes. Due, in part, to the fact that current SRMs generally target ligand binding domain （LBD）/AF2 and neglect intrinsically disordered （ID） N-terminal domain （NTD）/AF1, clinically relevant SRMs lack selectivity and are also prone to the development of resistance over time. Therefore, to maximize the efficacy of SHR-based therapeutics, the possibility of developing unique modulators that act to control AF1 activity must be considered. Recent studies targeting androgen receptor＇s （AR＇s） ID AF1 domain for the castration-resistant prostate cancer has provided the possibility of therapeutically targeting ID NTD/AF1 surfaces by allosteric modulations to achieve desired effects. In this review article, we discuss how inter- and intra- molecular allosteric regulations controlled by AR＇s structural flexibility and dynamics particularly the ID NTD/AF1 is an emerging area of investigation, which could be exploited for drug development and therapeutic targeting of prostate cancer.

关键词： allosteric regulation coregulatory proteins endocrine cancers intrinsically disordered proteins steroid hormone receptors structural dynamics transactivation activity

Discrete Exterior Calculus of Proteins and Their Cohomology

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Open Journal of Discrete Mathematics 2022年第3期12卷 47-63页

作者： Naoto Morikawa Genocript Zama Japan

This paper proposes a novel application of cohomology to protein structure analysis. Since proteins interact each other by forming transient protein complexes, their shape (e.g., shape complementarity) plays an important role in their functions. In our mathematical toy models, proteins are represented as a loop of triangles (2D model) or tetrahedra (3D model), where their interactions are defined as fusion of loops. The purpose of this paper is to describe the conditions for loop fusion using the language of cohomology. In particular, this paper uses cohomology to describe the conditions for “allosteric regulation”, which has been attracted attention in safer drug discovery. I hope that this paper will provide a new perspective on the mechanism of allosteric regulation. Advantages of the model include its topological nature. That is, we can deform the shape of loops by deforming the shape of triangles (or tetrahedra) as long as their folded structures are preserved. Another advantage is the simplicity of the “allosteric regulation” mechanism of the model. Furthermore, the effect of the “post-translational modification” can be understood as a resolution of singularities of a flow of triangles (or tetrahedra). No prior knowledge of either protein science, exterior calculus, or cohomology theory is required. The author hopes that this paper will facilitate the interaction between mathematics and protein science.

关键词： Discrete Differential Geometry Protein Structure Analysis Cohomology Class Exterior Derivative allosteric regulation

Discovery of Human STING allosteric Inhibitors

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Discovery of Human STING Allosteric Inhibitors

中国生物化学与分子生物学会第十二届全国会员代表大会暨2...

作者： Xiaobing Deng Xiaoyu Yu Sheng Bi Ying Liu Zhengfan Jiang Luhua Lai Peking-Tsinghua Center for Life Sciences Peking University College of Chemistry and Molecular Engineering Peking University School of Life Sciences Peking University

Stimulation of innate immune processes represents an attractive strategy to achieve multiple therapeutic outcomes including inhibition of virus replication,boosting antitumor immunity,enhancing vaccine immunogenicity,and improving autoimmunity.The recently discovered cGAS–STING pathway plays a crucial role in the production of type I IFNs caused by DNA.STING is the central signalling component.However,if STING is a good target for autoimmune diseases treatment is an open question.1 It is challenging to design inhibitors for such an adaptor protein.We applied Computer Aided Drug Design(CADD) to discover STING allosteric regulators.We first computationally identified a potential allosteric site in STING threedimensional structure.We then carried our virtual screening targeting this site and obtained a weak STING inhibitor R034.After optimization,compound 13100 showed enhanced inhibition of STING with an IC50 value of 20 M.13100 bound to hSTING with a dissociation constant of 17 M measured by SPR.We used whole cell thermal shift assay to verify that 13100 binds to hSTING in cell.Mutation of the key interacting residues of hSTING abolishes its inhibition response to 13100.Further study suggests that 13100 disrupts the interactions between STING and IRF3.To the best of our knowledge,our compounds are the first non-covalent STING inhibitors,which serve as useful probes to study cGAS-STING pathway.Using 13100 as a chemical probe,we proposed an auto-inhibition mechanism of STING,which was verified by mutation study and molecular dynamics simulations.

关键词： STING allosteric regulation Auto-inhibition

A multi-lock inhibitory mechanism for fine-tuning enzyme activities of the HECT family E3 ligases

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A multi-lock inhibitory mechanism for fine-tuning enzyme act...

中国生物化学与分子生物学会2019年全国学术会议暨学会...

作者： Zhen Wang Ziheng Liu Kang Zhu Zelin Shan Weiyi Yao Xing Chen Jingyu Li Shijing Huang Aihong Gu Wenyu Wen Institutes of Biomedical Sciences Shanghai Medical College Fudan University

The HECT type E3 ligases are key regulators of cell growth and proliferation, and malfunctions of these enzymes are associated with a broad range of human tumors and other diseases. The ligase activities of Nedd4 family E3s, the largest and best characterized subfamily of HECT E3s, are tightly controlled via auto-inhibition. However, the molecular mechanisms underlying Nedd4 E3s auto-inhibition and activation are poorly understood. We show that multiple WW domains play an inhibitory role by sequestering HECT using a multi-lock mechanism in most Nedd4 E3s, though each with a distinct mode. The structure of fully inhibited WWP1 reveals that many WWP1 mutations identified in cancer patients result in a partially active state with increased E3 ligase activity, and the WWP1 mutants likely promote cell migration by enhancement of ?Np63α degradation. We further demonstrate that WWP2 and Itch utilize a highly similar multi-lock autoinhibition mechanism as that utilized by WWP1, whereas Nedd4/4 L and Smurf2 utilize a slightly variant version. Binding of the Ndfip1 adaptor or JNK1-mediated phosphorylation relieves the auto-inhibition of Itch in a WW domain-dependent manner. Aberrant activation of Itch leads to migration defects of cortical neurons during development. Overall, these results reveal versatile autoinhibitory mechanisms that fine-tune the ligase activities of the HECT family enzymes.

关键词： Nedd4 family E3 ligases HECT ubiquitination allosteric regulation cell migration WWP1 ?Np63α Itch Nedd4/4L Smurf2

Force Distribution Analysis on MetJ Based on All-atom MD Simulation

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Force Distribution Analysis on MetJ Based on All-atom MD Sim...

2019中国化学会第十五届全国计算（机）化学学术会议

作者： Pengbo Song Zhirong Liu College of Chemistry and Molecular Engineering Peking University

The forces between atoms(or molecules) have important influence on protein properties. They cause conformational change when a protein binds with ligands, and thus affect the protein activity and are closely related to mechanisms of protein regulation in cells. In the past studies, people have paid much attention to the structure of proteins, but less attention has been paid to the forces. In this study, the force properties of MetJ, a methionine inhibitor, were investigated by means of all-atom Molecular Dynamics(MD) simulation and theoretical analysis. The decomposition of multi-body forces are analyzed, and a scheme was proposed where three-body and four-body forces can be decomposed into a sum of the pairwise forces along inter-atomic direction. An anisotropic network model(ANM) was used to calculate the residual force F and position fluctuation △R in Met J, which were shown to negatively correlated with each other and satisfy a universal relationship of

关键词： Force distribution analysis Molecular Dynamic simulation Elastic Network Model Methionine repressor allosteric regulation

Myosin-5a motor function is co-activated by two cargo adaptor proteins RILPL2 and melanophilin

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Myosin-5a motor function is co-activated by two cargo adapto...

中国生物化学与分子生物学会2019年全国学术会议暨学会...

作者： Qing-Juan Cao Ning Zhang Rui Zhou Lin-Lin Yao Xiang-dong Li Group of Cell Motility and Muscle Contraction State Key Laboratory of Integrated Management of Pest Insects and Rodents Institute of Zoology Chinese Academy of Sciences University of Chinese Academy of Sciences

Vertebrate myosin-5 a is an ATP-utilizing processive motor associated with the actin network and responsible for the transport and localization of several vesicle cargoes. To transport cargo efficiently and prevent futile ATP hydrolysis, myosin-5 a motor function must be tightly regulated. The globular tail domain(GTD) of myosin-5 a not only functions as the inhibitory domain, but also serves as the binding site for a number of cargo adaptor proteins, including melanophilin(Mlph) and Rab-interacting lysosomal proteinlike 2(RILPL2). In this study, using various biochemical approaches, including ATPase, single-molecule motility, and GST pulldown assays and analytical ultracentrifugation, we demonstrate that the binding of both Mlph and RILPL2 to the GTD of myosin-5 a is required for the activation of myosin-5 a motor function under physiological ionic conditions. We also found that this activation is regulated by the small GTPase Rab36, a binding partner of RILPL2. In summary, our results indicate that RILPL2 is required for Mlphmediated activation of Myo5 a motor activity under physiological conditions and that Rab36 promotes this activation. We propose that Rab36 stimulates RILPL2 to interact with the myosin-5 a GTD;this interaction then induces the exposure of the Mlph-binding site in the GTD, thereby enabling Mlph to interact with the GTD and activate myosin-5 a motor activity.

关键词： allosteric regulation melanophilin melanosome molecular motor myosin small GTPase vesicle transport

ASD:a comprehensive database of allosteric proteins and modulators

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ASD:a comprehensive database of allosteric proteins and modu...

第十一届全国计算（机）化学学术会议

作者：黄志敏 The Department of Pathophysiology and Chemical Biology Division of Shanghai Universities E-Institutes Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationShanghai Jiao-Tong University School of Medicine（SJTU-SM）Shanghai200025China

＜正＞Background:Allostery is the most direct,rapid and efficient way of regulating protein functions, ranging from the control of metabolic mechanisms to signal transduction pathways.Allostery describes the regulation of protein function,structure and/or flexibility induced by the binding of a ligand at a site topographically distinct from the orthosteric site.Such site is then defined as an allosteric site and the ligand binds to the allosteric site is known as allosteric modulator.However, an enormous amount of unsystematic allostery information has deterred scientists who could benefit from this field.

关键词： Allostery allosteric regulation allosteric site allosteric modulator

Structural insights into the activation of ubiquitin-specific protease 46 by WDR48 and WDR20

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Structural insights into the activation of ubiquitin-specifi...

中国生物化学与分子生物学会2019年全国学术会议暨学会...

作者： Hanwen Zhu Tianlong Zhang Fang Wang Jun Yang Jianping Ding State Key Laboratory of Molecular Biology National Center for Protein Science Shanghai Shanghai Science Research Center CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell Biology University of Chinese Academy of Sciences Chinese Academy of Sciences

Ubiquitination is an important and reversible post-translational modification that regulates the stability, localization and function of proteins in many cellular processes. Deubiquitinases are responsible for the removal of ubiquitin chains from proteins, and ubiquitin-specific proteases(USPs) are the largest family of deubiquitinases, some of which are regulated by WD40-repeat proteins. The deubiquitinating activity of USP46 can be activated by WDR48 and WDR20;however, the molecular mechanism remains elusive. We determined the crystal structure of the USP46-WDR48-WDR20 complex at 3.1 ? resolution and validated the functional roles of key residues involved in the assembly of the complex with both in vitro and in vivo functional assays. The structural and functional data demonstrate that the binding of WDR48 and WDR20 can activate the activity of USP46 independently and synergistically and plays an indispensible role in USP46-mediated deubiquitination of PHLPP1 in the Akt signaling pathway. Detailed comparison of all available USP46 and USP12 structures reveals that the WDR48 binding not only stabilizes the Fingers subdomain but also increases conformational flexibility of several structural elements surrounding the catalytic center;and the combined effects render a moderate activation of the USPs. The further binding of WDR20 largely restores the WDR48-binding induced conformational changes and stabilizes the conformations of those structural elements surrounding the catalytic center, and thus potentiates the activity of the USPs. These results provide new insights into the molecular mechanism of the activation of USPs by WD40-repeat proteins.

关键词： Ubiquitination deubiquitinases ubiquitin-specific proteases USP46 WD40-repeat protein allosteric regulation