[1,2,4]triazolo[4,3-a]phthalazines: inhibitors of diverse bromodomains. by Fedorov, O, Lingard, H, Wells, C, Monteiro, O, Picaud, S, Keates, T, Yapp, C, Philpott, M, Martin, S, Felletar, I, Marsden, B, Filippakopoulos, P, Müller, S, Knapp, S, Brennan, P

“…This new series of compounds is the first example of submicromolar inhibitors of bromodomains outside the BET subfamily. Representative compounds are active in cells exhibiting potent cellular inhibition activity in a FRAP model of CREBBP and chromatin association. …”

Discovery of a PCAF bromodomain chemical probe by Moustakim, M, Clark, P, Trulli, L, Fuentes de Arriba, A, Ehebauer, M, Chaikuad, A, Murphy, E, Mendez-Johnson, J, Daniels, D, Hou, C, Lin, Y, Walker, J, Hui, R, Yang, H, Dorrell, L, Rogers, C, Monteiro, O, Fedorov, O, Huber, K, Knapp, S, Heer, J, Dixon, D, Brennan, P

“…The p300/CBP-associated factor (PCAF) and related GCN5 bromodomain-containing lysine acetyl transferases are members of subfamily I of the bromodomain phylogenetic tree. Iterative cycles of rational inhibitor design and biophysical characterization led to the discovery of the triazolopthalazine-based L-45 (dubbed L-Moses) as the first potent, selective, and cell-active PCAF bromodomain (Brd) inhibitor. …”

Structures of Down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition. by Soundararajan, M, Roos, A, Savitsky, P, Filippakopoulos, P, Kettenbach, A, Olsen, J, Gerber, SA, Eswaran, J, Knapp, S, Elkins, J

“…We present crystal structures of one representative member of each DYRK subfamily: DYRK1A with an ATP-mimetic inhibitor and consensus peptide, and DYRK2 including NAPA and DH (DYRK homology) box regions. …”

Structures of down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition by Soundararajan, M, Roos, A, Savitsky, P, Filippakopoulos, P, Eswaran, J, Knapp, S, Elkins, J, Kettenbach, A, Gerber, SA, Olsen, J

“…We present crystal structures of one representative member of each DYRK subfamily: DYRK1A with an ATP-mimetic inhibitor and consensus peptide, and DYRK2 including NAPA and DH (DYRK homology) box regions. …”

Small-molecule inhibition of BRDT for male contraception. by Matzuk, M, McKeown, MR, Filippakopoulos, P, Li, Q, Ma, L, Agno, J, Lemieux, M, Picaud, S, Yu, R, Qi, J, Knapp, S, Bradner, J

“…Toward this objective, we explored the spermatogenic effects of a selective small-molecule inhibitor (JQ1) of the bromodomain and extraterminal (BET) subfamily of epigenetic reader proteins. Here, we report potent inhibition of the testis-specific member BRDT, which is essential for chromatin remodeling during spermatogenesis. …”

Conformational stability and activity of p73 require a second helix in the tetramerization domain. by Coutandin, D, Löhr, F, Niesen, F, Ikeya, T, Weber, T, Schäfer, B, Zielonka, E, Bullock, A, Yang, A, Güntert, P, Knapp, S, McKeon, F, Ou, H, Dötsch, V

“…No heterooligomerization between p53 and the p73/p63 subfamily was observed, supporting the notion of functional orthogonality within the p53 family.…”

Structure of the SOCS4-ElonginB/C complex reveals a distinct SOCS box interface and the molecular basis for SOCS-dependent EGFR degradation. by Bullock, A, Rodriguez, M, Debreczeni, J, Songyang, Z, Knapp, S

“…The N-terminal ESS helix functionally replaces the CIS/SOCS1-SOCS3 family C terminus in a distinct SH2-SOCS box interface that facilitates further interdomain packing between the extended N- and C-terminal regions characteristic for this subfamily. Using peptide arrays and calorimetry the STAT3 site in EGFR (pY(1092)) was identified as a high affinity SOCS4 substrate (K(D) = 0.5 microM) revealing a mechanism for EGFR degradation. …”

The crystal structure of human receptor protein tyrosine phosphatase kappa phosphatase domain 1. by Eswaran, J, Debreczeni, J, Longman, E, Barr, A, Knapp, S

“…RPTPkappa is a member of the R2A/IIb subfamily of RPTPs along with RPTPmu, RPTPrho, and RPTPlambda. …”

Conformational stability and activity of p73 require a second helix in the tetramerization domain. by Coutandin, D, Löhr, F, Niesen, F, Ikeya, T, Weber, T, Schäfer, B, Zielonka, E, Bullock, A, Yang, A, Güntert, P, Knapp, S, McKeon, F, Ou, H, Dötsch, V

“…No heterooligomerization between p53 and the p73/p63 subfamily was observed, supporting the notion of functional orthogonality within the p53 family.…”

Structural determinants of G-protein alpha subunit selectivity by regulator of G-protein signaling 2 (RGS2). by Kimple, A, Soundararajan, M, Hutsell, S, Roos, A, Urban, D, Setola, V, Temple, B, Roth, B, Knapp, S, Willard, F, Siderovski, D

“…Moreover, these three amino acids are seen to be evolutionarily conserved among organisms with modern cardiovascular systems, suggesting that RGS2 arose from the R4-subfamily of RGS proteins to have specialized activity as a potent and selective Galpha(q) GAP that modulates cardiovascular function.…”

Activation segment dimerization: a mechanism for kinase autophosphorylation of non-consensus sites. by Pike, A, Rellos, P, Niesen, F, Turnbull, A, Oliver, A, Parker, SA, Turk, B, Pearl, L, Knapp, S

“…Based on the presented structural and functional data, a model for specific activation segment phosphorylation at non-consensus substrate sites is proposed that is likely to be common to other kinases from diverse subfamilies.…”

Activation segment dimerization: a mechanism for kinase autophosphorylation of non-consensus sites by Pike, A, Rellos, P, Niesen, F, Turnbull, A, Oliver, A, Parker, S, Turk, B, Pearl, L, Knapp, S

“…Based on the presented structural and functional data, a model for specific activation segment phosphorylation at non-consensus substrate sites is proposed that is likely to be common to other kinases from diverse subfamilies.…”