查看“EED”的源代码

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            <strong>[[EED]]</strong>（<strong>[[Embryonic Ectoderm Development]]</strong>）是一种核心的[[表观遗传]]调节蛋白，属于<strong>[[Polycomb家族]]</strong>。作为<strong>[[PRC2复合物]]</strong>（[[Polycomb Repressive Complex 2]]）的三大核心亚基之一，[[EED]]通过其高度保守的<strong>[[WD40重复结构域]]</strong>发挥作用。其最关键的生物学功能是特异性识别并结合[[组蛋白H3]]第27位赖氨酸的三甲基化标记（<strong>[[H3K27me3]]</strong>），从而产生[[变构激活]]信号，极大地增强催化亚基<strong>[[EZH2]]</strong>的甲基转移酶活性。这种“[[正反馈]]”机制对于维持全基因组[[染色质]]的沉默状态至关重要。在临床研究中，[[EED]]的失调与多种[[血液肿瘤]]及[[实体瘤]]的发生密切相关，针对[[EED]]结合口袋开发的<strong>[[变构抑制剂]]</strong>已成为克服[[EZH2]]耐药的新型策略。
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            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">[[EED]]</div>
            <div style="font-size: 0.75em; opacity: 0.85; margin-top: 4px;">PRC2 关键变构调节因子 · 点击展开</div>
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                    <div style="width: 140px; height: 90px; background-color: #f1f5f9; display: flex; align-items: center; justify-content: center; color: #94a3b8; font-size: 0.8em; padding: 10px; text-align: center;">[[EED]]与[[H3K27me3]]肽段结合构象</div>
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                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">染色体位置：11q14.2</div>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0; width: 45%;">[[Entrez]]ID</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">1872</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">[[HGNC]]ID</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">3188</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">[[UniProt]]</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">O75530</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">蛋白质亚型</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">[[WD40重复]]蛋白</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">[[分子量]]</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">约50.2kDa</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569;">主要相互作用</th>
                    <td style="padding: 12px; color: #0f172a;">[[EZH2]]•[[SUZ12]]</td>
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    <h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">分子机制：PRC2复合物的驱动引擎</h2>
    
    <p style="margin: 15px 0; text-align: justify;">
        [[EED]]在[[染色质]]重塑过程中扮演着“感应器”与“扩音器”的双重角色：
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        <li style="margin-bottom: 12px;"><strong>[[H3K27me3]]识别：</strong>[[EED]]顶部的芳香族笼状结构（[[Aromatic Cage]]）能够精准识别已经存在的[[H3K27me3]]标记。这使得[[PRC2]]复合物能够定向结合到预先被修饰的[[基因组]]区域。</li>
        <li style="margin-bottom: 12px;"><strong>变构激活[[EZH2]]：</strong>一旦[[EED]]结合[[H3K27me3]]，它会诱导[[PRC2]]整体构象发生显著改变。这种信号通过[[EED]]与[[EZH2]]的[[SANT1]]结构域接触传递，使[[EZH2]]从低活性状态转化为高活性状态，从而快速扩散[[H3K27me3]]标记。</li>
        <li style="margin-bottom: 12px;"><strong>复合物组装：</strong>[[EED]]作为物理桥梁，与[[SUZ12]]共同构建了[[PRC2]]的基础骨架，支撑催化亚基[[EZH2]]的稳定存在。</li>
        <li style="margin-bottom: 12px;"><strong>调控发育：</strong>在胚胎发育早期，[[EED]]介导的[[X染色体失活]]及[[同源异型基因]]（[[Hox genes]]）的沉默是组织分化的前提。</li>
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    <h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">临床意义与病理学关联</h2>

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                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">病理领域</th>
                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #475569;">EED 异常特征</th>
                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #1e40af;">临床表型与风险</th>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[Weaver综合征]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">种系[[功能丧失型]]突变</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">表现为过度生长、特征性面容及[[智力发育迟缓]]。</td>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[弥漫性大B细胞淋巴瘤]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">过表达/功能获得</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">导致大量[[抑癌基因]]被异常沉默，促进恶性增殖。</td>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[耐药性研究]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">EZH2耐药突变补偿</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">即使[[EZH2]]催化位点突变，抑制[[EED]]结合口袋仍能瓦解[[PRC2]]活性。</td>
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    <h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">诊疗策略：靶向EED结合口袋</h2>
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        目前针对[[EED]]的开发策略是[[表观遗传]]药物研发的热点：
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        <li style="margin-bottom: 12px;"><strong>[[变构抑制剂]]：</strong>如<strong>[[MAK683]]</strong>。这些分子不结合[[EZH2]]的催化中心，而是结合[[EED]]的[[H3K27me3]]读取口袋。通过干扰[[EED]]与[[组蛋白]]的结合，使[[PRC2]]保持在失活状态。</li>
        <li style="margin-bottom: 12px;"><strong>克服[[SAM]]竞争耐药：</strong>传统的[[EZH2]]抑制剂（如[[他泽司他]]）易受细胞内高浓度[[SAM]]的影响产生耐药，而[[EED抑制剂]]的作用位点与[[SAM]]不同，提供了新的治疗窗口。</li>
        <li style="margin-bottom: 12px;"><strong>[[降解剂]]探索：</strong>利用[[PROTAC]]技术降解[[EED]]蛋白，可引起[[PRC2]]整个复合物的解体，其杀伤强度远高于单纯的酶抑制。</li>
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    <h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">关键相关概念</h2>
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            <li style="margin-bottom: 8px;"><strong>[[PRC2]]：</strong>由[[EZH1/2]]、[[EED]]和[[SUZ12]]构成的表观遗传沉默机器。</li>
            <li style="margin-bottom: 8px;"><strong>[[H3K27me3]]：</strong>抑制性染色质标记，[[EED]]是其最主要的“读者”蛋白。</li>
            <li style="margin-bottom: 8px;"><strong>[[WD40重复结构域]]：</strong>一种常见的蛋白质交互支架，在[[EED]]中形成七叶[[β-螺旋桨]]结构。</li>
            <li style="margin-bottom: 8px;"><strong>[[他泽司他]]：</strong>第一代[[EZH2]]抑制剂，常与新型[[EED]]抑制剂进行临床疗效对比。</li>
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        <span style="color: #0f172a; font-weight: bold; font-size: 1.05em; display: inline-block; margin-bottom: 15px;">学术参考文献与权威点评</span>
        
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            [1] <strong>Margueron R, et al. (2009).</strong> <em>Eed binding to trimethylated histone H3 lysine 27 allosterically activates the PRC2 complex.</em> <strong>[[Nature]]</strong>.[Academic Review]<br>
            <span style="color: #475569;">[权威点评]：该项开创性研究首次解析了EED如何通过变构效应激活PRC2的生物学奥秘。</span>
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            [2] <strong>Qi W, et al. (2017/2025 update).</strong> <em>Targeting the EED-H3K27me3 binding pocket blocks Polycomb-mediated gene silencing.</em> <strong>[[Nature Chemical Biology]]</strong>.<br>
            <span style="color: #475569;">[核心价值]：提供了针对EED开发小分子变构抑制剂的结构基础与药理验证数据。</span>
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            [[EED]] 染色质调控生态 · 知识图谱
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">关联亚基</td>
                <td style="padding: 10px 15px; color: #334155;">[[EZH2]]•[[SUZ12]]•[[RBBP4]]•[[PHF1]]</td>
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">治疗药物</td>
                <td style="padding: 10px 15px; color: #334155;">[[MAK683]]•[[A-395]]•[[EED226]]•[[瓦美妥司他]]</td>
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">战略实体</td>
                <td style="padding: 10px 15px; color: #334155;">[[Novartis]]•[[AbbVie]]•[[Daiichi Sankyo]]•[[Memorial Sloan Kettering]]</td>
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">研究前沿</td>
                <td style="padding: 10px 15px; color: #334155;">[[EED抑制剂克服EZH2获得性耐药]]•[[针对Weaver综合征的基因修饰研究]]•[[EED与非经典PRC1的交互]]</td>
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