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Lin Cheng

Bio: Lin Cheng is an academic researcher from University of Chicago. The author has contributed to research in topics: Medicine & Allosteric enzyme. The author has an hindex of 1, co-authored 1 publications receiving 2475 citations.

Papers
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Journal ArticleDOI
23 Dec 1998-Cell
TL;DR: Crystal structures of the human estrogen receptor alpha (hER alpha) ligand-binding domain (LBD) and the OHT-LBD complex reveal the two distinct mechanisms by which structural features of OHT promote this "autoinhibitory" helix 12 conformation.

2,581 citations

Journal ArticleDOI
TL;DR: The crystallographic and cryo-EM structures of CB1 bound to the positive allosteric modulator ZCZ011 revealallosteric modulation ofCB1 by rearrangement of the TM2 and TM3 transmembrane domains.

20 citations

Journal ArticleDOI
TL;DR: In this article , the signal bias profiles of the first-generation peptide drug octreotide and a new-generation small molecule paltusotine were analyzed by performing cryo-electron microscopy analysis of SSTR2-Gi complexes to determine how the drugs activate Sstr2 in a selective manner.
Abstract: Somatostatin receptor 2 (SSTR2) is highly expressed in neuroendocrine tumors and represents as a therapeutic target. Several peptide analogs mimicking the endogenous ligand somatostatin are available for clinical use, but poor therapeutic effects occur in a subset of patients, which may be correlated with subtype selectivity or cell surface expression. Here, we clarify the signal bias profiles of the first-generation peptide drug octreotide and a new-generation small molecule paltusotine by evaluating their pharmacological characteristics. We then perform cryo-electron microscopy analysis of SSTR2-Gi complexes to determine how the drugs activate SSTR2 in a selective manner. In this work, we decipher the mechanism of ligand recognition, subtype selectivity and signal bias property of SSTR2 sensing octreotide and paltusotine, which may aid in designing therapeutic drugs with specific pharmacological profiles against neuroendocrine tumors.

1 citations

Journal ArticleDOI
TL;DR: The cryo-electron microscopy method is applied to solve the structure of the S1P-S1PRs complex, and the mechanism of activation, selective drug recognition, and G-protein coupling is elucidated by using cell-based functional assays.
Abstract: Lysophospholipids (LPLs) are bioactive lipids that include sphingosine 1-phosphate (S1P), lysophosphatidic acid, etc. S1P, a metabolic product of sphingolipids in the cell membrane, is one of the best-characterized LPLs that regulates a variety of cellular physiological responses via signaling pathways mediated by sphingosine 1-phosphate receptors (S1PRs). This implicated that the S1P-S1PRs signaling system is a remarkable potential therapeutic target for disorders, including multiple sclerosis (MS), autoimmune disorders, cancer, inflammation, and even COVID-19. S1PRs, a small subset of the class A G-protein coupled receptor (GPCR) family, are composed of five subtypes: S1PR1, S1PR2, S1PR3, S1PR4, and S1PR5. The lack of detailed structural information, however, impedes the drug discovery targeting S1PRs. Here, we applied the cryo-electron microscopy method to solve the structure of the S1P-S1PRs complex, and elucidated the mechanism of activation, selective drug recognition, and G-protein coupling by using cell-based functional assays. Other lysophospholipid receptors (LPLRs) and GPCRs can also be studied using this strategy.

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Journal ArticleDOI
15 Feb 2001-Nature
TL;DR: A structural polymeric material with the ability to autonomically heal cracks is reported, which incorporates a microencapsulated healing agent that is released upon crack intrusion and polymerization of the healing agent is triggered by contact with an embedded catalyst, bonding the crack faces.
Abstract: Structural polymers are susceptible to damage in the form of cracks, which form deep within the structure where detection is difficult and repair is almost impossible. Cracking leads to mechanical degradation of fibre-reinforced polymer composites; in microelectronic polymeric components it can also lead to electrical failure. Microcracking induced by thermal and mechanical fatigue is also a long-standing problem in polymer adhesives. Regardless of the application, once cracks have formed within polymeric materials, the integrity of the structure is significantly compromised. Experiments exploring the concept of self-repair have been previously reported, but the only successful crack-healing methods that have been reported so far require some form of manual intervention. Here we report a structural polymeric material with the ability to autonomically heal cracks. The material incorporates a microencapsulated healing agent that is released upon crack intrusion. Polymerization of the healing agent is then triggered by contact with an embedded catalyst, bonding the crack faces. Our fracture experiments yield as much as 75% recovery in toughness, and we expect that our approach will be applicable to other brittle materials systems (including ceramics and glasses).

3,786 citations

Journal ArticleDOI
TL;DR: Many proteins that lack intrinsic globular structure under physiological conditions have now been recognized, and it appears likely that their rapid turnover, aided by their unstructured nature in the unbound state, provides a level of control that allows rapid and accurate responses of the cell to changing environmental conditions.

2,804 citations

Journal ArticleDOI
TL;DR: Using microarray-based profiling of isogenic prostate cancer xenograft models, it is found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy.
Abstract: Using microarray-based profiling of isogenic prostate cancer xenograft models, we found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy. This increase in androgen receptor mRNA and protein was both necessary and sufficient to convert prostate cancer growth from a hormone-sensitive to a hormone-refractory stage, and was dependent on a functional ligand-binding domain. Androgen receptor antagonists showed agonistic activity in cells with increased androgen receptor levels; this antagonist-agonist conversion was associated with alterations in the recruitment of coactivators and corepressors to the promoters of androgen receptor target genes. Increased levels of androgen receptor confer resistance to antiandrogens by amplifying signal output from low levels of residual ligand, and by altering the normal response to antagonists. These findings provide insight toward the design of new antiandrogens.

2,320 citations

Journal ArticleDOI
TL;DR: Based on their importance in biology and medicine, as well as the relatively simple mechanism of regulation, NR represent one of the most intensively studied and best-understood classes of transcription factors at the molecular level.
Abstract: Nuclear receptors (NR) comprise a family of transcription factors that regulate gene expression in a liganddependent manner. Members of the NR superfamily include receptors for steroid hormones, such as estrogens (ER) and glucocorticoids (GR), receptors for nonsteroidal ligands, such as thyroid hormones (TR) and retinoic acid (RAR), as well as receptors that bind diverse products of lipid metabolism, such as fatty acids and prostaglandins (for review, see Beato et al. 1995; Chambon 1995; Mangelsdorf and Evans 1995). The NR superfamily also includes a large number of so-called orphan receptors for which regulatory ligands have not been identified (Mangelsdorf and Evans 1995). Although many orphan receptors are likely to be regulated by small-molecular-weight ligands, other mechanisms of regulation, such as phosphorylation (Hammer et al. 1999; Tremblay et al. 1999) have also proven to be of importance. Remarkably, the sequence of the Caenorhabditis elegans genome has revealed the presence of >200 members of the NR family, suggesting a critical role of these proteins in environmental adaptation (Sluder et al. 1999). Although mammalian genomes are unlikely to contain such a large complement of these factors, >24 distinct classes of NR have been identified in humans, and these factors exert diverse roles in the regulation of growth, development, and homeostasis. Based on their importance in biology and medicine, as well as the relatively simple mechanism of regulation, NR represent one of the most intensively studied and best-understood classes of transcription factors at the molecular level. Members of the NR family regulate transcription by several mechanisms (Fig. 1). Nuclear receptors can activate or repress target genes by binding directly to DNA response elements as homoor heterodimers or by binding to other classes of DNA-bound transcription factors. A subset of NRs, including TR and RAR, can actively repress target genes in the presence or absence of ligand binding, and many NR have been demonstrated to inhibit transcription in a ligand-dependent manner by antagonizing the transcriptional activities of other classes of transcription factors. These activities have been linked to interactions with general classes of molecules that appear to serve coactivator or corepressor function. In this review, we will discuss recent progress concerning the molecular mechanisms by which NR cofactor interactions serve to activate or repress transcription.

2,200 citations

Journal ArticleDOI
TL;DR: The recent successful generation of double knockout, or alpha beta ERKO mice of both sexes, suggests that this receptor is also not essential to survival and was most likely not a compensatory factor in the survival of the alpha ERKO.
Abstract: All scientific investigations begin with distinct objectives: first is the hypothesis upon which studies are undertaken to disprove, and second is the overall aim of obtaining further information, from which future and more precise hypotheses may be drawn Studies focusing on the generation and use of gene-targeted animal models also apply these goals and may be loosely categorized into sequential phases that become apparent as the use of the model progresses Initial studies of knockout models often focus on the plausibility of the model based on prior knowledge and whether the generation of an animal lacking the particular gene will prove lethal or not Upon the successful generation of a knockout, confirmatory studies are undertaken to corroborate previously established hypotheses of the function of the disrupted gene product As these studies continue, observations of unpredicted phenotypes or, more likely, the lack of a phenotype that was expected based on models put forth from past investigations are noted Often the surprising phenotype is due to the loss of a gene product that is downstream from the functions of the disrupted gene, whereas the lack of an expected phenotype may be due to compensatory roles filled by alternate mechanisms As the descriptive studies of the knockout continue, use of the model is often shifted to the role as a unique research reagent, to be used in studies that 1) were not previously possible in a wild-type model; 2) aimed at finding related proteins or pathways whose existence or functions were previously masked; or 3) the subsequent effects of the gene disruption on related physiological and biochemical systems The alpha ERKO mice continue to satisfy the confirmatory role of a knockout quite well As summarized in Table 4, the phenotypes observed in the alpha ERKO due to estrogen insensitivity have definitively illustrated several roles that were previously believed to be dependent on functional ER alpha, including 1) the proliferative and differentiative actions critical to the function of the adult female reproductive tract and mammary gland; 2) as an obligatory component in growth factor signaling in the uterus and mammary gland; 3) as the principal steroid involved in negative regulation of gonadotropin gene transcription and LH levels in the hypothalamic-pituitary axis; 4) as a positive regulator of PR expression in several tissues; 5) in the positive regulation of PRL synthesis and secretion from the pituitary; 6) as a promotional factor in oncogene-induced mammary neoplasia; and 7) as a crucial component in the differentiation and activation of several behaviors in both the female and male The list of unpredictable phenotypes in the alpha ERKO must begin with the observation that generation of an animal lacking a functional ER alpha gene was successful and produced animals of both sexes that exhibit a life span comparable to wild-type The successful generation of beta ERKO mice suggests that this receptor is also not essential to survival and was most likely not a compensatory factor in the survival of the alpha ERKO In support of this is our recent successful generation of double knockout, or alpha beta ERKO mice of both sexes The precise defects in certain components of male reproduction, including the production of abnormal sperm and the loss of intromission and ejaculatory responses that were observed in the alpha ERKO, were quite surprising In turn, certain estrogen pathways in the alpha ERKO female appear intact or unaffected, such as the ability of the uterus to successfully exhibit a progesterone-induced decidualization response, and the possible maintenance of an LH surge system in the hypothalamus [ABSTRACT TRUNCATED]

2,053 citations