Crystal structures of human RIP2 kinase catalytic domain complexed with ATP-competitive inhibitors: Foundations for understanding inhibitor selectivity

Charnley Adam K.; Convery Maire A.; Shah Ami Lakdawala; Jones Emma; Hardwicke Philip; Bridges Angela; Ouellette Michael; Totoritis Rachel; Schwartz Benjamin; King Bryan W.; Wisnoski David D.; Kang James; Eidam Patrick M.; Votta Bartholomew J.; Gough Peter J.; Marquis Robert W.; Bertin John; Casillas Linda

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Crystal structures of human RIP2 kinase catalytic domain complexed with ATP-competitive inhibitors: Foundations for understanding inhibitor selectivity

机译：人RIP2激酶催化结构域与ATP竞争性抑制剂复合的晶体结构：了解抑制剂选择性的基础

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Receptor interacting protein 2 (RIP2) is an intracellular kinase and key signaling partner for the pattern recognition receptors NOD1 and NOD2 (nucleotide-binding oligomerization domain-containing proteins 1 and 2). As such, RIP2 represents an attractive target to probe the role of these pathways in disease. In an effort to design potent and selective inhibitors of RIP2 we established a crystallographic system and determined the structure of the RIP2 kinase domain in an apo form and also in complex with multiple inhibitors including AMP-PCP (beta,gamma-Methyleneadenosine 5'-triphosphate, a non-hydrolysable adenosine triphosphate mimic) and structurally diverse ATP competitive chemotypes identified via a high-throughput screening campaign. These structures represent the first set of diverse RIP2-inhibitor co-crystal structures and demonstrate that the protein possesses the ability to adopt multiple DFG-in as well as DFG-out and C-helix out conformations. These structures reveal key protein-inhibitor structural insights and serve as the foundation for establishing a robust structure-based drug design effort to identify both potent and highly selective inhibitors of RIP2 kinase. (C) 2015 Elsevier Ltd. All rights reserved.

机译：受体相互作用蛋白2（RIP2）是细胞内激酶和模式识别受体NOD1和NOD2（包含核苷酸结合寡聚域的蛋白1和2）的关键信号转导伙伴。这样，RIP2代表了一个有吸引力的靶标，以探讨这些途径在疾病中的作用。为了设计RIP2的有效和选择性抑制剂，我们建立了晶体学系统，并确定了apo形式的RIP2激酶域结构，并与包括AMP-PCP（β，γ-亚甲基腺苷5'-三磷酸酯）在内的多种抑制剂配合使用（一种不可水解的三磷酸腺苷模拟物）和通过高通量筛选活动确定的结构多样的ATP竞争化学型。这些结构代表了第一组不同的RIP2抑制剂共晶体结构，并证明该蛋白质具有采用多种DFG输入以及DFG输出和C螺旋输出构象的能力。这些结构揭示了关键的蛋白质抑制剂的结构见解，并为建立基于结构的稳健药物设计工作奠定了基础，以鉴定RIP2激酶的强效和高选择性抑制剂。（C）2015 Elsevier Ltd.保留所有权利。

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《Bioorganic and medicinal chemistry》 |2015年第21期|共7页
作者
Charnley Adam K.; Convery Maire A.; Shah Ami Lakdawala; Jones Emma; Hardwicke Philip; Bridges Angela; Ouellette Michael; Totoritis Rachel; Schwartz Benjamin; King Bryan W.; Wisnoski David D.; Kang James; Eidam Patrick M.; Votta Bartholomew J.; Gough Peter J.; Marquis Robert W.; Bertin John; Casillas Linda;
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RIP2; RIPK2; RICK; CARD3; CARDIAK; X-ray cocrystal structure; Kinase structure; Kinase inhibitor; Structure-based drug design; Inhibitor selectivity;

机译：RIP2;RIPK2;RICK;CARD3;CARDIAK;X射线共晶结构;激酶结构;激酶抑制剂;基于结构的药物设计;抑制剂选择性;

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1. Crystal structures of human RIP2 kinase catalytic domain complexed with ATP-competitive inhibitors: Foundations for understanding inhibitor selectivity [J] . Charnley Adam K., Convery Maire A., Shah Ami Lakdawala, Bioorganic and medicinal chemistry . 2015,第21期

机译：人RIP2激酶催化结构域与ATP竞争性抑制剂复合的晶体结构：了解抑制剂选择性的基础
2. X-ray structure of human stromelysin catalytic domain complexed with nonpeptide inhibitors: implications for inhibitor selectivity. [J] . Pavlovsky AG, Williams MG, Ye QZ, Protein Science: A Publication of the Protein Society . 1999,第7期

机译：与非肽抑制剂复合的人类溶菌素催化域的X射线结构：对抑制剂选择性的影响。
3. Structure-Based Virtual Screening of High-Affinity ATP-Competitive Inhibitors Against Human Lemur Tyrosine Kinase-3 (LMTK3) Domain: A Novel Therapeutic Target for Breast Cancer [J] . Sarma Himakshi, Mattaparthi Venkata Satish Kumar Interdisciplinary Sciences: Computational Life Sciences . 2019,第3期

机译：基于结构的高亲和力ATP竞争性抑制剂对人类狐猴激酶-3（LMTK3）结构域的虚拟筛选：一种新的乳腺癌治疗靶标
4. A Collision Induced Unfolding Assay for Dierentiating ATP-Competitive and Allosteric Protein Tyrosine Kinase Inhibitors [C] . James E. Keating, Jessica N. Rabuck-Gibbons, Brandon T. Ruotolo ASMS Conference on Mass Spectrometry and Allied Topics . 2015

机译：针对ATP竞争性和颠振蛋白酪氨酸激酶抑制剂的固化性诱导诱导展开测定
5. Characterization and Exploitation of Bidirectional Allosteric Coupling in Multi-Domain Tyrosine Kinases using Conformation-Selective ATP-Competitive Inhibitors. [D] . Register, Ames C. 2016

机译：使用构象选择性ATP竞争性抑制剂在多域酪氨酸激酶中双向变构偶联的表征和开发。
6. X-ray structure of human stromelysin catalytic domain complexed with nonpeptide inhibitors: implications for inhibitor selectivity. [O] . A. G. Pavlovsky, M. G. Williams, Q. Z. Ye, 1999

机译：与非肽抑制剂复合的人类溶菌素催化域的X射线结构：对抑制剂选择性的影响。
7. X-ray structure of human stromelysin catalytic domain complexed with nonpeptide inhibitors: implications for inhibitor selectivity. [O] . Pavlovsky, A. G., Williams, M. G., Ye, Q. Z., 1999

机译：与非肽抑制剂复合的人类溶菌素催化域的X射线结构：对抑制剂选择性的影响。

Crystal structures of human RIP2 kinase catalytic domain complexed with ATP-competitive inhibitors: Foundations for understanding inhibitor selectivity

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