ABSTRACT:The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays important roles in cell proliferation, growth, and survival. Hyperactivated PI3K is frequently found in a wide variety of human cancers, validating it as a promising target for cancer therapy. We determined the crystal structure of the human PI3Kα−PI103 complex to unravel molecular interactions. Based on the structure, substitution at the R 1 position of the phenol portion of PI103 was demonstrated to improve binding affinity via forming a new H-bond with Lys802 at the bottom of the ATP catalytic site. Interestingly, the crystal structure of the PI3Kα−9d complex revealed that the flexibility of Lys802 can also induce additional space at the catalytic site for further modification. Thus, these crystal structures provide a molecular basis for the strong and specific interactions and demonstrate the important role of Lys802 in the design of novel PI3Kα inhibitors. KEYWORDS: PI3K, PI103, crystal structure, drug design, cancer therapy T he lipid kinase family of phosphatidylinositol 3-kinases (PI3Ks) plays pivotal roles in many cellular processes, including proliferation, survival, differentiation, and metabolism. 1−3 Class I PI3K, the best physiologically, biochemically, and structurally characterized member of the PI3K family, consists of four isoforms, α, β, γ, and δ. Each isoform is a heterodimer that comprises a p110 catalytic subunit and a p85 regulatory subunit. Upon insulin and growth factor stimulation, PI3Ks phosphorylate phosphatidylinositol-3,4-bisphosphate (PIP2) to produce phosphatidylinositol-3,4,5-triphosphate (PIP3). The cellular level of PIP3 is also tightly regulated by phosphatases, such as the phosphatase and tensin homologue (PTEN), which dephosphorylates PIP3 back to PIP2. 4,5 The PI3K pathway is frequently deregulated in a wide range of tumor types as a result of hyperactivation of upstream growth factor signaling, mutation, or loss of PTEN, 6 and oncogenic mutations in PIK3CA, 7 which provides further evidence of the role of PI3K in tumorigenesis. Moreover, accumulating evidence indicates that hyperactivation of PI3Kα is inextricably linked to cancer survival and resistance to existing therapies in a great proportion of human cancers. 8 Therefore, targeting PI3Ks with small-molecular-weight inhibitors provides an attractive opportunity for cancer therapy and for overcoming resistance to current therapies, and thus, significant efforts have recently been made to develop PI3K inhibitors. 9 With multiple ongoing efforts in academic and industrial organizations to develop clinically relevant inhibitors against PI3K, a number of inhibitors have already entered clinical trials. 2,10 PI103 is one of the first synthesized PI3K inhibitors; it belongs to the pyridinylfuranopyrimidine class and inhibits PI3K in an ATP-competitive manner with selectivity toward PI3Kα. 11 PI103 has already demonstrated significant antitumor activity against several human tumor xenografts, especially those with well-established abnormalities in the P...

In order to realize the high precision alignment of a catadioptric infrared optical system and improve the imaging quality of the system, a method of using visible light interferometer, infrared interferometer and articulated arm to align infrared optical system was proposed in this paper. First, the characteristics of the infrared optical system were introduced, and the alignment tolerances of each optical element were simulated and analyzed. Then, by aligning the R-C system of primary mirror assembly, the primary mirror assembly reference was extended to the mechanical mechanism, which provided the reference for subsequent precise alignment. The articulated arm was used to monitor the three-dimensional position of the lens assembly, in order to ensure the accuracy of the lens assembly initial alignment. Finally, the infrared interferometer was used to monitor the wavefront aberration of the system, and the relationship between the misalignment of the lens assembly and the zernike coefficient of the system was established, which could guide the alignment work, clear the direction of alignment, and finally realize the accurate alignment of the optical system. The experimental results indicated that the wavefront aberration values of the optical system were better than 1/15 λ (λ =3.39 μm), and each field amplitude transfer function(MTF) was better than 0.25, which met the requirements of imaging quality. It provided a feasible way for the catadioptric infrared optical system to be aligned, and also could be extended to the alignment of the remote sensors of similar structures space flight and aviation.

This electronic document is a "live" template. The various components of your paper [title, text, heads, etc.] are already defined on the style sheet, as illustrated by the portions given in this document. DO NOT USE SPECIAL CHARACTERS, SYMBOLS, OR MATH IN YOUR TITLE OR ABSTRACT.

This paper describes the structure and performance of phase comparison ranging radar, and mainly discusses its application in the continuous phase phase comparison ranging radar, introduces the basic working principle of phase comparison ranging radar, analyzes the hardware configuration and software design of radar tracking control system based on DPS, as well as detailed discusses the design and implementation of the software in section. The test results show that the whole system has better met the design requirements.