5u5p

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==Crystal Structure and X-ray Diffraction Data Collection of Importin-alpha from Mus Musculus Complexed with a PMS2 NLS Peptide==
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==Crystal Structure and X-ray Diffraction Data Collection of Importin-alpha from Mus Musculus Complexed with a MLH1 NLS Peptide==
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<StructureSection load='5u5p' size='340' side='right' caption='[[5u5p]], [[Resolution|resolution]] 2.17&Aring;' scene=''>
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<StructureSection load='5u5p' size='340' side='right'caption='[[5u5p]], [[Resolution|resolution]] 2.17&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5u5p]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5U5P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5U5P FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5u5p]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5U5P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5U5P FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DTT:2,3-DIHYDROXY-1,4-DITHIOBUTANE'>DTT</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.171&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5u5r|5u5r]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DTT:2,3-DIHYDROXY-1,4-DITHIOBUTANE'>DTT</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5u5p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u5p OCA], [http://pdbe.org/5u5p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5u5p RCSB], [http://www.ebi.ac.uk/pdbsum/5u5p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5u5p ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5u5p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u5p OCA], [https://pdbe.org/5u5p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5u5p RCSB], [https://www.ebi.ac.uk/pdbsum/5u5p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5u5p ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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[[http://www.uniprot.org/uniprot/MLH1_HUMAN MLH1_HUMAN]] Muir-Torre syndrome;Hereditary nonpolyposis colon cancer. Defects in MLH1 are the cause of hereditary non-polyposis colorectal cancer type 2 (HNPCC2) [MIM:[http://omim.org/entry/609310 609310]]. Mutations in more than one gene locus can be involved alone or in combination in the production of the HNPCC phenotype (also called Lynch syndrome). Most families with clinically recognized HNPCC have mutations in either MLH1 or MSH2 genes. HNPCC is an autosomal, dominantly inherited disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early onset colorectal carcinoma (CRC) and extra-colonic cancers of the gastrointestinal, urological and female reproductive tracts. HNPCC is reported to be the most common form of inherited colorectal cancer in the Western world, and accounts for 15% of all colon cancers. Cancers in HNPCC originate within benign neoplastic polyps termed adenomas. Clinically, HNPCC is often divided into two subgroups. Type I: hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II: patients have an increased risk for cancers in certain tissues such as the uterus, ovary, breast, stomach, small intestine, skin, and larynx in addition to the colon. Diagnosis of classical HNPCC is based on the Amsterdam criteria: 3 or more relatives affected by colorectal cancer, one a first degree relative of the other two; 2 or more generation affected; 1 or more colorectal cancers presenting before 50 years of age; exclusion of hereditary polyposis syndromes. The term 'suspected HNPCC' or 'incomplete HNPCC' can be used to describe families who do not or only partially fulfill the Amsterdam criteria, but in whom a genetic basis for colon cancer is strongly suspected.<ref>PMID:11427529</ref> <ref>PMID:7757073</ref> <ref>PMID:11429708</ref> <ref>PMID:8571956</ref> <ref>PMID:8566964</ref> <ref>PMID:8872463</ref> <ref>PMID:8797773</ref> <ref>PMID:9311737</ref> <ref>PMID:8993976</ref> <ref>PMID:9218993</ref> <ref>PMID:9048925</ref> <ref>PMID:9272156</ref> <ref>PMID:9067757</ref> <ref>PMID:9298827</ref> <ref>PMID:9399661</ref> <ref>PMID:9326924</ref> <ref>PMID:9718327</ref> <ref>PMID:9559627</ref> <ref>PMID:10627141</ref> <ref>PMID:10660333</ref> <ref>PMID:10671064</ref> <ref>PMID:9833759</ref> <ref>PMID:10375096</ref> <ref>PMID:9927034</ref> <ref>PMID:10323887</ref> <ref>PMID:10480359</ref> <ref>PMID:10598809</ref> <ref>PMID:10386556</ref> <ref>PMID:10413423</ref> <ref>PMID:10777691</ref> <ref>PMID:10713887</ref> <ref>PMID:10882759</ref> <ref>PMID:12132870</ref> <ref>PMID:11726306</ref> <ref>PMID:11139242</ref> <ref>PMID:11748856</ref> <ref>PMID:12095971</ref> <ref>PMID:12373605</ref> <ref>PMID:11781295</ref> <ref>PMID:11839723</ref> <ref>PMID:11793442</ref> <ref>PMID:11754112</ref> <ref>PMID:12200596</ref> <ref>PMID:11870161</ref> <ref>PMID:12362047</ref> <ref>PMID:12658575</ref> <ref>PMID:12655562</ref> <ref>PMID:14635101</ref> <ref>PMID:15139004</ref> <ref>PMID:15365995</ref> <ref>PMID:15365996</ref> <ref>PMID:14961575</ref> <ref>PMID:15064764</ref> <ref>PMID:16083711</ref> <ref>PMID:16451135</ref> <ref>PMID:17510385</ref> <ref>PMID:17301300</ref> <ref>PMID:18561205</ref> Defects in MLH1 are a cause of mismatch repair cancer syndrome (MMRCS) [MIM:[http://omim.org/entry/276300 276300]]; also known as Turcot syndrome or brain tumor-polyposis syndrome 1 (BTPS1). MMRCS is an autosomal dominant disorder characterized by malignant tumors of the brain associated with multiple colorectal adenomas. Skin features include sebaceous cysts, hyperpigmented and cafe au lait spots.<ref>PMID:11427529</ref> <ref>PMID:7661930</ref> <ref>PMID:17440981</ref> Defects in MLH1 are a cause of Muir-Torre syndrome (MRTES) [MIM:[http://omim.org/entry/158320 158320]]. Rare autosomal dominant disorder characterized by sebaceous neoplasms and visceral malignancy.<ref>PMID:8751876</ref> Note=Defects in MLH1 may contribute to lobular carcinoma in situ (LCIS), a non-invasive neoplastic disease of the breast.<ref>PMID:11369138</ref> Defects in MLH1 are a cause of susceptibility to endometrial cancer (ENDMC) [MIM:[http://omim.org/entry/608089 608089]]. Note=Some epigenetic changes can be transmitted unchanged through the germline (termed 'epigenetic inheritance'). Evidence that this mechanism occurs in humans is provided by the identification of individuals in whom 1 allele of the MLH1 gene is epigenetically silenced throughout the soma (implying a germline event). These individuals are affected by HNPCC but does not have identifiable mutations in MLH1, even though it is silenced, which demonstrates that an epimutation can phenocopy a genetic disease.
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[https://www.uniprot.org/uniprot/MLH1_HUMAN MLH1_HUMAN] Muir-Torre syndrome;Hereditary nonpolyposis colon cancer. Defects in MLH1 are the cause of hereditary non-polyposis colorectal cancer type 2 (HNPCC2) [MIM:[https://omim.org/entry/609310 609310]. Mutations in more than one gene locus can be involved alone or in combination in the production of the HNPCC phenotype (also called Lynch syndrome). Most families with clinically recognized HNPCC have mutations in either MLH1 or MSH2 genes. HNPCC is an autosomal, dominantly inherited disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early onset colorectal carcinoma (CRC) and extra-colonic cancers of the gastrointestinal, urological and female reproductive tracts. HNPCC is reported to be the most common form of inherited colorectal cancer in the Western world, and accounts for 15% of all colon cancers. Cancers in HNPCC originate within benign neoplastic polyps termed adenomas. Clinically, HNPCC is often divided into two subgroups. Type I: hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II: patients have an increased risk for cancers in certain tissues such as the uterus, ovary, breast, stomach, small intestine, skin, and larynx in addition to the colon. Diagnosis of classical HNPCC is based on the Amsterdam criteria: 3 or more relatives affected by colorectal cancer, one a first degree relative of the other two; 2 or more generation affected; 1 or more colorectal cancers presenting before 50 years of age; exclusion of hereditary polyposis syndromes. The term 'suspected HNPCC' or 'incomplete HNPCC' can be used to describe families who do not or only partially fulfill the Amsterdam criteria, but in whom a genetic basis for colon cancer is strongly suspected.<ref>PMID:11427529</ref> <ref>PMID:7757073</ref> <ref>PMID:11429708</ref> <ref>PMID:8571956</ref> <ref>PMID:8566964</ref> <ref>PMID:8872463</ref> <ref>PMID:8797773</ref> <ref>PMID:9311737</ref> <ref>PMID:8993976</ref> <ref>PMID:9218993</ref> <ref>PMID:9048925</ref> <ref>PMID:9272156</ref> <ref>PMID:9067757</ref> <ref>PMID:9298827</ref> <ref>PMID:9399661</ref> <ref>PMID:9326924</ref> <ref>PMID:9718327</ref> <ref>PMID:9559627</ref> <ref>PMID:10627141</ref> <ref>PMID:10660333</ref> <ref>PMID:10671064</ref> <ref>PMID:9833759</ref> <ref>PMID:10375096</ref> <ref>PMID:9927034</ref> <ref>PMID:10323887</ref> <ref>PMID:10480359</ref> <ref>PMID:10598809</ref> <ref>PMID:10386556</ref> <ref>PMID:10413423</ref> <ref>PMID:10777691</ref> <ref>PMID:10713887</ref> <ref>PMID:10882759</ref> <ref>PMID:12132870</ref> <ref>PMID:11726306</ref> <ref>PMID:11139242</ref> <ref>PMID:11748856</ref> <ref>PMID:12095971</ref> <ref>PMID:12373605</ref> <ref>PMID:11781295</ref> <ref>PMID:11839723</ref> <ref>PMID:11793442</ref> <ref>PMID:11754112</ref> <ref>PMID:12200596</ref> <ref>PMID:11870161</ref> <ref>PMID:12362047</ref> <ref>PMID:12658575</ref> <ref>PMID:12655562</ref> <ref>PMID:14635101</ref> <ref>PMID:15139004</ref> <ref>PMID:15365995</ref> <ref>PMID:15365996</ref> <ref>PMID:14961575</ref> <ref>PMID:15064764</ref> <ref>PMID:16083711</ref> <ref>PMID:16451135</ref> <ref>PMID:17510385</ref> <ref>PMID:17301300</ref> <ref>PMID:18561205</ref> Defects in MLH1 are a cause of mismatch repair cancer syndrome (MMRCS) [MIM:[https://omim.org/entry/276300 276300]; also known as Turcot syndrome or brain tumor-polyposis syndrome 1 (BTPS1). MMRCS is an autosomal dominant disorder characterized by malignant tumors of the brain associated with multiple colorectal adenomas. Skin features include sebaceous cysts, hyperpigmented and cafe au lait spots.<ref>PMID:11427529</ref> <ref>PMID:7661930</ref> <ref>PMID:17440981</ref> Defects in MLH1 are a cause of Muir-Torre syndrome (MRTES) [MIM:[https://omim.org/entry/158320 158320]. Rare autosomal dominant disorder characterized by sebaceous neoplasms and visceral malignancy.<ref>PMID:8751876</ref> Note=Defects in MLH1 may contribute to lobular carcinoma in situ (LCIS), a non-invasive neoplastic disease of the breast.<ref>PMID:11369138</ref> Defects in MLH1 are a cause of susceptibility to endometrial cancer (ENDMC) [MIM:[https://omim.org/entry/608089 608089]. Note=Some epigenetic changes can be transmitted unchanged through the germline (termed 'epigenetic inheritance'). Evidence that this mechanism occurs in humans is provided by the identification of individuals in whom 1 allele of the MLH1 gene is epigenetically silenced throughout the soma (implying a germline event). These individuals are affected by HNPCC but does not have identifiable mutations in MLH1, even though it is silenced, which demonstrates that an epimutation can phenocopy a genetic disease.
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/MLH1_HUMAN MLH1_HUMAN]] Heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR). DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH6) binding to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS-heteroduplex ternary complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2. It introduces single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the newly mutated DNA strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts physically with the clamp loader subunits of DNA polymerase III, suggesting that it may play a role to recruit the DNA polymerase III to the site of the MMR. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can lead to apoptosis in case of major DNA damages. Heterodimerizes with MLH3 to form MutL gamma which plays a role in meiosis.<ref>PMID:16873062</ref> <ref>PMID:18206974</ref> [[http://www.uniprot.org/uniprot/IMA1_MOUSE IMA1_MOUSE]] Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1. Binds specifically and directly to substrates containing either a simple or bipartite NLS motif. Docking of the importin/substrate complex to the nuclear pore complex (NPC) is mediated by KPNB1 through binding to nucleoporin FxFG repeats and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin-beta and the three components separate and importin-alpha and -beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus.
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[https://www.uniprot.org/uniprot/MLH1_HUMAN MLH1_HUMAN] Heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR). DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH6) binding to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS-heteroduplex ternary complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2. It introduces single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the newly mutated DNA strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts physically with the clamp loader subunits of DNA polymerase III, suggesting that it may play a role to recruit the DNA polymerase III to the site of the MMR. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can lead to apoptosis in case of major DNA damages. Heterodimerizes with MLH3 to form MutL gamma which plays a role in meiosis.<ref>PMID:16873062</ref> <ref>PMID:18206974</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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MLH1 and PMS2 proteins form the MutLalpha heterodimer, which plays a major role in DNA mismatch repair (MMR) in humans. Mutations in MMR-related proteins are associated with cancer, especially with colon cancer. The N-terminal region of MutLalpha comprises the N-termini of PMS2 and MLH1 and, similarly, the C-terminal region of MutLalpha is composed by the C-termini of PMS2 and MLH1, and the two are connected by linker region. The nuclear localization sequences (NLSs) necessary for the nuclear transport of the two proteins are found in this linker region. However, the exact NLS sequences have been controversial, with different sequences reported, particularly for MLH1. The individual components are not imported efficiently, presumably due to their C-termini masking their NLSs. In order to gain insights into the nuclear transport of these proteins, we solved the crystal structures of importin-alpha bound to peptides corresponding to the supposed NLSs of MLH1 and PMS2 and performed isothermal titration calorimetry to study their binding affinities. Both putative MLH1 and PMS2 NLSs can bind to importin-alpha as monopartite NLSs, which is in agreement with some previous studies. However, MLH1-NLS has the highest affinity measured by a natural NLS peptide, suggesting a major role of MLH1 protein in nuclear import compared to PMS2. Finally, the role of MLH1 and PMS2 in the nuclear transport of the MutLalpha heterodimer is discussed.
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DNA mismatch repair proteins MLH1 and PMS2 can be imported to the nucleus by a classical nuclear import pathway.,de Barros AC, Takeda AAS, Dreyer TR, Velazquez-Campoy A, Kobe B, Fontes MRM Biochimie. 2018 Mar;146:87-96. doi: 10.1016/j.biochi.2017.11.013. Epub 2017 Nov, 24. PMID:29175432<ref>PMID:29175432</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 5u5p" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Importin 3D structures|Importin 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Barros, A C]]
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[[Category: Homo sapiens]]
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[[Category: Dreyer, T R]]
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[[Category: Large Structures]]
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[[Category: Fontes, M R]]
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[[Category: Mus musculus]]
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[[Category: Kobe, B]]
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[[Category: Barros AC]]
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[[Category: Takeda, A A]]
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[[Category: Dreyer TR]]
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[[Category: Velazquez-Campoy, A]]
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[[Category: Fontes MR]]
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[[Category: Importin-alpha]]
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[[Category: Kobe B]]
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[[Category: Mlh1]]
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[[Category: Takeda AA]]
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[[Category: Nl]]
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[[Category: Velazquez-Campoy A]]
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[[Category: Nuclear transport]]
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[[Category: Transport protein]]
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Current revision

Crystal Structure and X-ray Diffraction Data Collection of Importin-alpha from Mus Musculus Complexed with a MLH1 NLS Peptide

PDB ID 5u5p

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