2x1n | pdb_00002x1n

TRUNCATION AND OPTIMISATION OF PEPTIDE INHIBITORS OF CDK2, CYCLIN A THROUGH STRUCTURE GUIDED DESIGN

spinqualitylabelsall models 2x1n, resolution 2.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2x1n is a 5 chain structure with sequence from Homo sapiens. This structure supersedes the now removed PDB entry 2wha. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: X1N NonStd Res: ACE, NH2, PFF Related: 1h08, 1pye, 2vth, 2b53, 1v1k, 1ke7, 1okv, 1h25, 1pxk, 2wih, 2bhh, 2vta, 2uue, 1gz8, 1e1v, 1ol2, 1h27, 1jsv, 2wha, 2b52, 1ke5, 1fin, 2c5o, 2c68, 2vtt, 1p2a, 2vtq, 2c4g, 1h1q, 1w0x, 2w05, 1pxo, 1ke9, 2a0c, 1hck, 1jsu, 1pxn, 2uze, 2v0d, 2vtm, 1oiq, 1h1r, 2iw8, 1hcl, 1pw2, 1gih, 2whb, 2vtn, 2w06, 1jst, 1oiu, 1b38, 1pxm, 1fq1, 1vyw, 1h1p, 2wma, 2c69, 1urc, 1pxi, 2c6i, 2wxv, 1ykr, 2w17, 2uzd, 2c6k, 2c5y, 1wcc, 2j9m, 1vyz, 2vti, 1jvp, 1w98, 2wip, 1pkd, 1p5e, 2vts, 2c5p, 2uzn, 2b54, 1ke6, 1pxj, 2uzl, 2cci, 2bkz, 2g9x, 1y91, 2iw6, 1gij, 1r78, 1h0v, 2iw9, 1w8c, 1buh, 2bpm, 2bts, 1fvv, 1okw, 2vtp, 2a4l, 2c6t, 1fvt, 1qmz, 2w1h, 2vu3, 2b55, 1ogu, 1pf8, 1h1s, 2c5v, 2jgz, 2bhe, 1urw, 1oiy, 2c6l, 1f5q, 2c6o, 2vtl, 1ol1, 1h01, 2wfy, 2uzb, 1oir, 1oi9, 2vtj, 2cjm, 2c5x, 2wev, 2c5n, 2c6m, 1oit, 2v22, 1gy3, 1di8, 1gii, 2vv9, 2wpa, 1e9h, 2wmb, 2vto, 1dm2, 1h24, 2uzo, 2exm, 1h00, 2clx, 1pxp, 2cch, 1b39, 2btr, 1aq1, 1h0w, 1g5s, 1ckp, 1ke8, 1h28, 1pxl, 2vtr, 1h26, 1e1x, 1h07, 1y8y Activity: Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Resources: FirstGlance, OCA, RCSB, PDBsum Function [CDK2_HUMAN] Serine/threonine-protein kinase involved in the control of the cell cycle; essential for meiosis, but dispensable for mitosis. Phosphorylates CTNNB1, USP37, p53/TP53, NPM1, CDK7, RB1, BRCA2, MYC, NPAT, EZH2. Interacts with cyclins A, B1, B3, D, or E. Triggers duplication of centrosomes and DNA. Acts at the G1-S transition to promote the E2F transcriptional program and the initiation of DNA synthesis, and modulates G2 progression; controls the timing of entry into mitosis/meiosis by controlling the subsequent activation of cyclin B/CDK1 by phosphorylation, and coordinates the activation of cyclin B/CDK1 at the centrosome and in the nucleus. Crucial role in orchestrating a fine balance between cellular proliferation, cell death, and DNA repair in human embryonic stem cells (hESCs). Activity of CDK2 is maximal during S phase and G2; activated by interaction with cyclin E during the early stages of DNA synthesis to permit G1-S transition, and subsequently activated by cyclin A2 (cyclin A1 in germ cells) during the late stages of DNA replication to drive the transition from S phase to mitosis, the G2 phase. EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing. Phosphorylates CABLES1 (By similarity). Cyclin E/CDK2 prevents oxidative stress-mediated Ras-induced senescence by phosphorylating MYC. Involved in G1-S phase DNA damage checkpoint that prevents cells with damaged DNA from initiating mitosis; regulates homologous recombination-dependent repair by phosphorylating BRCA2, this phosphorylation is low in S phase when recombination is active, but increases as cells progress towards mitosis. In response to DNA damage, double-strand break repair by homologous recombination a reduction of CDK2-mediated BRCA2 phosphorylation. Phosphorylation of RB1 disturbs its interaction with E2F1. NPM1 phosphorylation by cyclin E/CDK2 promotes its dissociates from unduplicated centrosomes, thus initiating centrosome duplication. Cyclin E/CDK2-mediated phosphorylation of NPAT at G1-S transition and until prophase stimulates the NPAT-mediated activation of histone gene transcription during S phase. Required for vitamin D-mediated growth inhibition by being itself inactivated. Involved in the nitric oxide- (NO) mediated signaling in a nitrosylation/activation-dependent manner. USP37 is activated by phosphorylation and thus triggers G1-S transition. CTNNB1 phosphorylation regulates insulin internalization. [CCNA2_HUMAN] Essential for the control of the cell cycle at the G1/S (start) and the G2/M (mitosis) transitions. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Following the recent discovery and development of 2-anilino-4-(thiazol-5-yl)pyrimidine cyclin dependent kinase (CDK) inhibitors, a program was initiated to evaluate related ring-constrained analogues, specifically, 2-methyl- and 2-amino-N-aryl-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amines for inhibition of CDKs. Here we report the rational design, synthesis, structure-activity relationships (SARs), and cellular mode-of-action profile of these second generation CDK inhibitors. Many of the analogues from this chemical series inhibit CDKs with very low nanomolar K(i) values. The most potent compound reported in this study inhibits CDK2 with an IC(50) of 0.7 nM ([ATP] = 100 microM). Furthermore, an X-ray crystal structure of 2-methyl-N-(3-(nitro)phenyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amine (11g), a representative from the chemical series in complex with cyclin A-CDK2, is reported, confirming the design rationale and expected binding mode within the CDK2 ATP binding pocket. Design, synthesis, and evaluation of 2-methyl- and 2-amino-N-aryl-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amines as ring-constrained 2-anilino-4-(thiazol-5-yl)pyrimidine cyclin-dependent kinase inhibitors.,McIntyre NA, McInnes C, Griffiths G, Barnett AL, Kontopidis G, Slawin AM, Jackson W, Thomas M, Zheleva DI, Wang S, Blake DG, Westwood NJ, Fischer PM J Med Chem. 2010 Mar 11;53(5):2136-45. PMID:20146435 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cell division protein kinase 2 Cyclin

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