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2cch

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Revision as of 08:47, 23 May 2018

The crystal structure of CDK2 cyclin A in complex with a substrate peptide derived from CDC modified with a gamma-linked ATP analogue

Structural highlights

2cch is a 6 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
NonStd Res:
Related:	1aq1, 1b38, 1b39, 1buh, 1ckp, 1di8, 1dm2, 1e1v, 1e1x, 1e9h, 1f5q, 1fin, 1fq1, 1fvt, 1fvv, 1g5s, 1gih, 1gii, 1gij, 1gy3, 1gz8, 1h00, 1h01, 1h07, 1h08, 1h0v, 1h0w, 1h1p, 1h1q, 1h1r, 1h1s, 1h24, 1h25, 1h26, 1h27, 1h28, 1hck, 1hcl, 1jst, 1jsu, 1jsv, 1jvp, 1ke5, 1ke6, 1ke7, 1ke8, 1ke9, 1ogu, 1oi9, 1oiq, 1oir, 1oit, 1oiu, 1oiy, 1oku, 1okv, 1okw, 1ol1, 1ol2, 1p2a, 1p5e, 1pf8, 1pkd, 1pw2, 1pxi, 1pxj, 1pxk, 1pxl, 1pxm, 1pxn, 1pxo, 1pxp, 1pye, 1qmz, 1r78, 1urc, 1urw, 1v1k, 1vyw, 1vyz, 1w0x, 1w8c, 1w98, 1wcc, 1y8y, 1y91, 2b52, 2b53, 2b54, 2b55, 2bhe, 2bhh, 2bkz, 2bpm, 2btr, 2bts, 2c4g, 2c5n, 2c5o, 2c5p, 2c5t, 2c5v, 2c5x, 2c5y, 2c68, 2c69, 2c6i, 2c6k, 2c6l, 2c6m, 2c6o, 2c6t, 2exm
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[CDC6_HUMAN] Defects in CDC6 are the cause of Meier-Gorlin syndrome type 5 (MGORS5) [MIM:613805]. MGORS5 is a syndrome characterized by bilateral microtia, aplasia/hypoplasia of the patellae, and severe intrauterine and postnatal growth retardation with short stature and poor weight gain. Additional clinical findings include anomalies of cranial sutures, microcephaly, apparently low-set and simple ears, microstomia, full lips, highly arched or cleft palate, micrognathia, genitourinary tract anomalies, and various skeletal anomalies. While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal.^[1]

Function

[CDC6_HUMAN] Involved in the initiation of DNA replication. Also participates in checkpoint controls that ensure DNA replication is completed before mitosis is initiated. [CCNA2_HUMAN] Essential for the control of the cell cycle at the G1/S (start) and the G2/M (mitosis) transitions.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Phospho-CDK2/cyclin A, a kinase that is active in cell cycle S phase, contains an RXL substrate recognition site that is over 40 A from the catalytic site. The role of this recruitment site, which enhances substrate affinity and catalytic efficiency, has been investigated using peptides derived from the natural substrates, namely CDC6 and p107, and a bispeptide inhibitor in which the gamma-phosphate of ATP is covalently attached by a linker to the CDC6 substrate peptide. X-ray studies with a 30-residue CDC6 peptide in complex with pCDK2/cyclin A showed binding of a dodecamer peptide at the recruitment site and a heptapeptide at the catalytic site, but no density for the linking 11 residues. Kinetic studies established that the CDC6 peptide had an 18-fold lower Km compared with heptapeptide substrate and that this effect required the recruitment peptide to be covalently linked to the substrate peptide. X-ray studies with the CDC6 bispeptide showed binding of the dodecamer at the recruitment site and the modified ATP in two alternative conformations at the catalytic site. The CDC6 bispeptide was a potent inhibitor competitive with both ATP and peptide substrate of pCDK2/cyclin A activity against a heptapeptide substrate (Ki = 0.83 nm) but less effective against RXL-containing substrates. We discuss how localization at the recruitment site (KD 0.4 microm) leads to increased catalytic efficiency and the design of a potent inhibitor. The notion of a flexible linker between the sites, which must have more than a minimal number of residues, provides an explanation for recognition and discrimination against different substrates.

The role of the phospho-CDK2/cyclin A recruitment site in substrate recognition.,Cheng KY, Noble ME, Skamnaki V, Brown NR, Lowe ED, Kontogiannis L, Shen K, Cole PA, Siligardi G, Johnson LN J Biol Chem. 2006 Aug 11;281(32):23167-79. Epub 2006 May 17. PMID:16707497^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Bicknell LS, Bongers EM, Leitch A, Brown S, Schoots J, Harley ME, Aftimos S, Al-Aama JY, Bober M, Brown PA, van Bokhoven H, Dean J, Edrees AY, Feingold M, Fryer A, Hoefsloot LH, Kau N, Knoers NV, Mackenzie J, Opitz JM, Sarda P, Ross A, Temple IK, Toutain A, Wise CA, Wright M, Jackson AP. Mutations in the pre-replication complex cause Meier-Gorlin syndrome. Nat Genet. 2011 Feb 27;43(4):356-9. doi: 10.1038/ng.775. PMID:21358632 doi:10.1038/ng.775
↑ Cheng KY, Noble ME, Skamnaki V, Brown NR, Lowe ED, Kontogiannis L, Shen K, Cole PA, Siligardi G, Johnson LN. The role of the phospho-CDK2/cyclin A recruitment site in substrate recognition. J Biol Chem. 2006 Aug 11;281(32):23167-79. Epub 2006 May 17. PMID:16707497 doi:http://dx.doi.org/10.1074/jbc.M600480200

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2cch"

@@ Line 1: / Line 1: @@
-==THE CRYSTAL STRUCTURE OF CDK2 CYCLIN A IN COMPLEX WITH A SUBSTRATE PEPTIDE DERIVED FROM CDC MODIFIED WITH A GAMMA-LINKED ATP ANALOGUE==
+==The crystal structure of CDK2 cyclin A in complex with a substrate peptide derived from CDC modified with a gamma-linked ATP analogue==
 <StructureSection load='2cch' size='340' side='right' caption='[[2cch]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
 == Structural highlights ==
@@ Line 6: / Line 7: @@
 <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1aq1|1aq1]], [[1b38|1b38]], [[1b39|1b39]], [[1buh|1buh]], [[1ckp|1ckp]], [[1di8|1di8]], [[1dm2|1dm2]], [[1e1v|1e1v]], [[1e1x|1e1x]], [[1e9h|1e9h]], [[1f5q|1f5q]], [[1fin|1fin]], [[1fq1|1fq1]], [[1fvt|1fvt]], [[1fvv|1fvv]], [[1g5s|1g5s]], [[1gih|1gih]], [[1gii|1gii]], [[1gij|1gij]], [[1gy3|1gy3]], [[1gz8|1gz8]], [[1h00|1h00]], [[1h01|1h01]], [[1h07|1h07]], [[1h08|1h08]], [[1h0v|1h0v]], [[1h0w|1h0w]], [[1h1p|1h1p]], [[1h1q|1h1q]], [[1h1r|1h1r]], [[1h1s|1h1s]], [[1h24|1h24]], [[1h25|1h25]], [[1h26|1h26]], [[1h27|1h27]], [[1h28|1h28]], [[1hck|1hck]], [[1hcl|1hcl]], [[1jst|1jst]], [[1jsu|1jsu]], [[1jsv|1jsv]], [[1jvp|1jvp]], [[1ke5|1ke5]], [[1ke6|1ke6]], [[1ke7|1ke7]], [[1ke8|1ke8]], [[1ke9|1ke9]], [[1ogu|1ogu]], [[1oi9|1oi9]], [[1oiq|1oiq]], [[1oir|1oir]], [[1oit|1oit]], [[1oiu|1oiu]], [[1oiy|1oiy]], [[1oku|1oku]], [[1okv|1okv]], [[1okw|1okw]], [[1ol1|1ol1]], [[1ol2|1ol2]], [[1p2a|1p2a]], [[1p5e|1p5e]], [[1pf8|1pf8]], [[1pkd|1pkd]], [[1pw2|1pw2]], [[1pxi|1pxi]], [[1pxj|1pxj]], [[1pxk|1pxk]], [[1pxl|1pxl]], [[1pxm|1pxm]], [[1pxn|1pxn]], [[1pxo|1pxo]], [[1pxp|1pxp]], [[1pye|1pye]], [[1qmz|1qmz]], [[1r78|1r78]], [[1urc|1urc]], [[1urw|1urw]], [[1v1k|1v1k]], [[1vyw|1vyw]], [[1vyz|1vyz]], [[1w0x|1w0x]], [[1w8c|1w8c]], [[1w98|1w98]], [[1wcc|1wcc]], [[1y8y|1y8y]], [[1y91|1y91]], [[2b52|2b52]], [[2b53|2b53]], [[2b54|2b54]], [[2b55|2b55]], [[2bhe|2bhe]], [[2bhh|2bhh]], [[2bkz|2bkz]], [[2bpm|2bpm]], [[2btr|2btr]], [[2bts|2bts]], [[2c4g|2c4g]], [[2c5n|2c5n]], [[2c5o|2c5o]], [[2c5p|2c5p]], [[2c5t|2c5t]], [[2c5v|2c5v]], [[2c5x|2c5x]], [[2c5y|2c5y]], [[2c68|2c68]], [[2c69|2c69]], [[2c6i|2c6i]], [[2c6k|2c6k]], [[2c6l|2c6l]], [[2c6m|2c6m]], [[2c6o|2c6o]], [[2c6t|2c6t]], [[2exm|2exm]]</td></tr>
-<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=2cch FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2cch OCA], [http://pdbe.org/2cch PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2cch RCSB], [http://www.ebi.ac.uk/pdbsum/2cch PDBsum]</span></td></tr>
+<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=2cch FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2cch OCA], [http://pdbe.org/2cch PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2cch RCSB], [http://www.ebi.ac.uk/pdbsum/2cch PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2cch ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 16: / Line 17: @@
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/cc/2cch_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/cc/2cch_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
-</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2cch ConSurf].
 <div style="clear:both"></div>
 <div style="background-color:#fffaf0;">
@@ Line 33: / Line 34: @@
 ==See Also==
-*[[Cell division protein kinase|Cell division protein kinase]]
 *[[Cyclin|Cyclin]]
+*[[Cyclin-dependent kinase|Cyclin-dependent kinase]]
 == References ==
 <references/>
@@ Line 59: / Line 60: @@
 [[Category: Peptide specificity]]
 [[Category: Phosphorylation]]
+[[Category: Polymorphism]]
 [[Category: Protein kinase]]
 [[Category: Recruitment]]

2cch

From Proteopedia

Revision as of 08:47, 23 May 2018

The crystal structure of CDK2 cyclin A in complex with a substrate peptide derived from CDC modified with a gamma-linked ATP analogue

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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