2rmb: Difference between revisions

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[[Image:2rmb.gif|left|200px]]<br />

[[Image:2rmb.gif|left|200px]]<br /><applet load="2rmb" size="350" color="white" frame="true" align="right" spinBox="true"

<applet load="2rmb" size="~~450~~" color="white" frame="true" align="right" spinBox="true"

caption="2rmb, resolution 2.1Å" />

'''CRYSTAL STRUCTURES OF CYCLOPHILIN A COMPLEXED WITH CYCLOSPORIN A AND N-METHYL-4-[(E)-2-BUTENYL]-4,4-DIMETHYLTHREONINE CYCLOSPORIN A'''<br />

==Overview==

BACKGROUND: Cyclophilin (CyP) is a ubiquitious intracellular protein that, binds the immunosuppressive drug cyclosporin A (CsA). CyP-CsA forms a, ternary complex with calcineurin and thereby inhibits T-cell activation., CyP also has enzymatic activity, catalyzing the cis-trans isomerization of, peptidyl-prolyl amide bonds. RESULTS: We have determined the structure of, human cyclophilin A (CyPA) complexed with CsA to 2.1 A resolution. We also, report here the structure of CyPA complexed with an analog of CsA, CsA, (MeBm2t1-CsA), which binds less well to CyPA, but has increased, immunosuppressive activity. Comparison of these structures with previously, determined structures of unligated CyPA and CyPA complexed with a, candidate substrate for the isomerase activity, the dipeptide AlaPro, reveals that subtle conformational changes occur in both CsA and CyPA on, complex formation. CONCLUSIONS: MeBm2t1-CsA binds to CyPA in an, essentially similar manner to CsA. The 100-fold weaker affinity of its, binding may be attributable to the close contact between MeBmt1 and the, active site residue Ala103 of CyPA, which causes small conformational, changes in both protein and drug. One change, the slight movement of, MeLeu6 in CsA relative to MeBm2t1-CsA, may be at least partially, responsible for the higher affinity of the CyPA-MeBm2t1-CsA complex for, calcineurin. Our comparison between CyPA-CsA and CyPA-AlaPro suggests that, CsA is probably not an analog of the natural substrate, confirming that, the catalytic activity of CyPA is not related to its role in, immunosuppression either structurally or functionally.

BACKGROUND: Cyclophilin (CyP) is a ubiquitious intracellular protein that binds the immunosuppressive drug cyclosporin A (CsA). CyP-CsA forms a ternary complex with calcineurin and thereby inhibits T-cell activation. CyP also has enzymatic activity, catalyzing the cis-trans isomerization of peptidyl-prolyl amide bonds. RESULTS: We have determined the structure of human cyclophilin A (CyPA) complexed with CsA to 2.1 A resolution. We also report here the structure of CyPA complexed with an analog of CsA, CsA (MeBm2t1-CsA), which binds less well to CyPA, but has increased immunosuppressive activity. Comparison of these structures with previously determined structures of unligated CyPA and CyPA complexed with a candidate substrate for the isomerase activity, the dipeptide AlaPro, reveals that subtle conformational changes occur in both CsA and CyPA on complex formation. CONCLUSIONS: MeBm2t1-CsA binds to CyPA in an essentially similar manner to CsA. The 100-fold weaker affinity of its binding may be attributable to the close contact between MeBmt1 and the active site residue Ala103 of CyPA, which causes small conformational changes in both protein and drug. One change, the slight movement of MeLeu6 in CsA relative to MeBm2t1-CsA, may be at least partially responsible for the higher affinity of the CyPA-MeBm2t1-CsA complex for calcineurin. Our comparison between CyPA-CsA and CyPA-AlaPro suggests that CsA is probably not an analog of the natural substrate, confirming that the catalytic activity of CyPA is not related to its role in immunosuppression either structurally or functionally.

==About this Structure==

2RMB is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Active as [http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] Full crystallographic information is available from [http://~~ispc~~.weizmann.ac.il/oca-bin/ocashort?id=2RMB OCA].

2RMB is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Active as [http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2RMB OCA].

==Reference==

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[[Category: complex (isomerase/immunosuppressant)]]

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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:48:24 2008''

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-[[Image:2rmb.gif|left|200px]]<br />
+[[Image:2rmb.gif|left|200px]]<br /><applet load="2rmb" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="2rmb" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="2rmb, resolution 2.1&Aring;" />
 '''CRYSTAL STRUCTURES OF CYCLOPHILIN A COMPLEXED WITH CYCLOSPORIN A AND N-METHYL-4-[(E)-2-BUTENYL]-4,4-DIMETHYLTHREONINE CYCLOSPORIN A'''<br />
 ==Overview==
-BACKGROUND: Cyclophilin (CyP) is a ubiquitious intracellular protein that, binds the immunosuppressive drug cyclosporin A (CsA). CyP-CsA forms a, ternary complex with calcineurin and thereby inhibits T-cell activation., CyP also has enzymatic activity, catalyzing the cis-trans isomerization of, peptidyl-prolyl amide bonds. RESULTS: We have determined the structure of, human cyclophilin A (CyPA) complexed with CsA to 2.1 A resolution. We also, report here the structure of CyPA complexed with an analog of CsA, CsA, (MeBm2t1-CsA), which binds less well to CyPA, but has increased, immunosuppressive activity. Comparison of these structures with previously, determined structures of unligated CyPA and CyPA complexed with a, candidate substrate for the isomerase activity, the dipeptide AlaPro, reveals that subtle conformational changes occur in both CsA and CyPA on, complex formation. CONCLUSIONS: MeBm2t1-CsA binds to CyPA in an, essentially similar manner to CsA. The 100-fold weaker affinity of its, binding may be attributable to the close contact between MeBmt1 and the, active site residue Ala103 of CyPA, which causes small conformational, changes in both protein and drug. One change, the slight movement of, MeLeu6 in CsA relative to MeBm2t1-CsA, may be at least partially, responsible for the higher affinity of the CyPA-MeBm2t1-CsA complex for, calcineurin. Our comparison between CyPA-CsA and CyPA-AlaPro suggests that, CsA is probably not an analog of the natural substrate, confirming that, the catalytic activity of CyPA is not related to its role in, immunosuppression either structurally or functionally.
+BACKGROUND: Cyclophilin (CyP) is a ubiquitious intracellular protein that binds the immunosuppressive drug cyclosporin A (CsA). CyP-CsA forms a ternary complex with calcineurin and thereby inhibits T-cell activation. CyP also has enzymatic activity, catalyzing the cis-trans isomerization of peptidyl-prolyl amide bonds. RESULTS: We have determined the structure of human cyclophilin A (CyPA) complexed with CsA to 2.1 A resolution. We also report here the structure of CyPA complexed with an analog of CsA, CsA (MeBm2t1-CsA), which binds less well to CyPA, but has increased immunosuppressive activity. Comparison of these structures with previously determined structures of unligated CyPA and CyPA complexed with a candidate substrate for the isomerase activity, the dipeptide AlaPro, reveals that subtle conformational changes occur in both CsA and CyPA on complex formation. CONCLUSIONS: MeBm2t1-CsA binds to CyPA in an essentially similar manner to CsA. The 100-fold weaker affinity of its binding may be attributable to the close contact between MeBmt1 and the active site residue Ala103 of CyPA, which causes small conformational changes in both protein and drug. One change, the slight movement of MeLeu6 in CsA relative to MeBm2t1-CsA, may be at least partially responsible for the higher affinity of the CyPA-MeBm2t1-CsA complex for calcineurin. Our comparison between CyPA-CsA and CyPA-AlaPro suggests that CsA is probably not an analog of the natural substrate, confirming that the catalytic activity of CyPA is not related to its role in immunosuppression either structurally or functionally.
 ==About this Structure==
-RMB is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Active as [http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2RMB OCA].
+RMB is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Active as [http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2RMB OCA].
 ==Reference==
@@ Line 19: / Line 18: @@
 [[Category: complex (isomerase/immunosuppressant)]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 23:37:52 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:48:24 2008''