Analysis of the binding of mixed lineage leukemia 1 (MLL1) and histone 3 peptides to WD repeat domain 5 (WDR5) for the design of inhibitors of the MLL1-WDR5 interaction.
Analysis of the binding of mixed lineage leukemia 1 (MLL1) and histone 3 peptides to WD repeat domain 5 (WDR5) for the design of inhibitors of the MLL1-WDR5 interaction.
复制标题
DOI：
10.1021/jm100139b
复制
发表时间：
2010-07-22
影响因子：
7.3
通讯作者：
Wang S
中科院分区：
文献类型：
--
作者：
Karatas H;Townsend EC;Bernard D;Dou Y;Wang S
MLL 1是一种组蛋白3赖氨酸4（H3 K4）甲基转移酶，是一个有前途的新的癌症治疗靶点。MLL 1的催化活性通过由MLL 1、WDR 5、RbBP 5和Ash 2L组成的核心复合物的形成来调节。WDR 5和MLL 1之间的相互作用在MLL 1的H3 K4甲基转移酶活性的调节中起着重要作用，并且使用小分子靶向这种相互作用可能代表有吸引力的治疗策略。在这项研究中，我们已经确定了MLL 1中的必需元素，其高亲和力结合WDR 5。我们的数据表明，MLL 1与WDR 5的高亲和力结合的最小要素是-CO-ARA-NH-基序和两个分子内氢键，稳定该基序的构象。基于MLL 1和H3序列设计了两种3聚体肽Ac-ARA-NH 2和Ac-ART-NH 2，并分别实现了对WDR 5的Ki值为120和20 nM。我们的研究为设计有效的肽模拟物和非肽化合物提供了具体的基础，通过靶向MLL 1和WDR 5的相互作用来抑制MLL 1的活性。
MLL1 is a histone 3 lysine 4 (H3K4) methyltransferase and a promising new cancer therapeutic target. The catalytic activity of MLL1 is regulated by the formation of a core complex consisting of MLL1, WDR5, RbBP5, and Ash2L. The interaction between WDR5 and MLL1 plays an essential role in regulation of the H3K4 methyltransferase activity of MLL1 and targeting this interaction using small molecules may represent an attractive therapeutic strategy. In this study, we have defined the essential elements in MLL1 required for its high-affinity binding to WDR5. Our data showed that the minimal elements crucial for high-affinity binding of MLL1 to WDR5 are –CO-ARA-NH–motif and two intramolecular hydrogen bonds that stabilize the conformation of this motif. Two 3-mer peptides, Ac-ARA-NH2 and Ac-ART-NH2, were designed based upon MLL1 and H3 sequences and achieved Ki values of 120 and 20 nM to WDR5, respectively. Our study provides a concrete basis for the design of potent peptidomimetics and nonpeptidic compounds to inhibit MLL1 activity by targeting the MLL1 and WDR5 interaction.
登录
查看更多内容
影响因子：
5.3
作者：
Hsieh, JJD;Ernst, P;Korsmeyer, SJ
通讯作者：
Korsmeyer, SJ
影响因子：
20.3
作者：
Faber, Joerg;Krivtsov, Andrei V.;Armstrong, Scott A.
通讯作者：
Armstrong, Scott A.
影响因子：
5.4
作者：
Mishra, Bibhu P.;Ansari, Khairul I.;Mandal, Subhrangsu S.
通讯作者：
Mandal, Subhrangsu S.
影响因子：
8.4
作者：
DEVITA, G;BARBA, P;CILLO, C
通讯作者：
CILLO, C
影响因子：
16.8
作者：
Couture, Jean-Francois;Collazo, Evys;Trievel, Raymond C.
通讯作者：
Trievel, Raymond C.