2gw5: Difference between revisions

Revision as of 18:35, 21 February 2008

Crystal Structure of LIR-2 (ILT4) at 1.8 : differences from LIR-1 (ILT2) in regions implicated in the binding of the Cytomegalovirus class I MHC homolog UL18

OverviewOverview

BACKGROUND: Leukocyte Immunoglobulin-like Receptor-1 (LIR-1) and LIR-2 (also known as ILT2 and ILT4 respectively) are highly related cell surface receptors that bind a broad range of class I MHC molecules with low (microM) affinities. Expressed on monocytic cells and macrophages, both molecules transmit inhibitory signals after binding ligands. In addition to binding host class I MHC, the LIR-1 molecule, which is also expressed on lymphoid tissues, binds with a high (nM) affinity to UL18, a class I MHC homolog encoded by Human Cytomegalovirus (HCMV). In comparison, LIR-2 binds UL18 only weakly (microM KD). To understand how HCMV preferentially targets the more broadly expressed LIR-1 molecule, we determined the crystal structure of a ligand-binding fragment of LIR-2, and compared this to the existing high-resolution crystal structure of LIR-1. RESULTS: Recombinant LIR-2 (domains 1 and 2) was produced in E. coli and crystallized using streak seeding to optimize the crystal morphology. A data set complete to 1.8 A was collected at 100 K from a single crystal in the P4(1)2(1)2 spacegroup. The structure was solved by molecular replacement, using a search model based on the LIR-1 structure. CONCLUSIONS: The overall structure of LIR-2 D1D2 resembles both LIR-1, and Killer Inhibitory Receptors, in that the A strand in each domain forms hydrogen bonds to both beta sheets, and there is a sharp angle between the two immunoglobulin-like domains. However, differences from LIR-1 are observed in each domain, with two key changes apparent in the ligand-binding domain, D1. The region corresponding to the residue 44-57 helix of LIR-1 adopts a topology distinct from that of both LIR-1 and the KIR structures, involving a shortened 310 helix. Secondly, the predicted UL18 binding region of LIR-1 is altered substantially in LIR-2: the 76-84 loop mainchain is displaced 11 A with respect to LIR-1, and Tyrosine 38 adopts an alternative rotamer conformation. In summary, the structure of LIR-2 has revealed significant differences to LIR-1, including ones that may help to explain the >1000-fold lower affinity of LIR-2 for UL18.

About this StructureAbout this Structure

2GW5 is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.

ReferenceReference

Crystal structure of LIR-2 (ILT4) at 1.8 A: differences from LIR-1 (ILT2) in regions implicated in the binding of the Human Cytomegalovirus class I MHC homolog UL18., Willcox BE, Thomas LM, Chapman TL, Heikema AP, West AP Jr, Bjorkman PJ, BMC Struct Biol. 2002 Oct 11;2:6. PMID:12390682

Page seeded by OCA on Thu Feb 21 17:35:58 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
-[[Image:2gw5.gif|left|200px]]<br />
+[[Image:2gw5.gif|left|200px]]<br /><applet load="2gw5" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="2gw5" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="2gw5, resolution 1.80&Aring;" />
 '''Crystal Structure of LIR-2 (ILT4) at 1.8 : differences from LIR-1 (ILT2) in regions implicated in the binding of the Cytomegalovirus class I MHC homolog UL18'''<br />
 ==Overview==
-BACKGROUND: Leukocyte Immunoglobulin-like Receptor-1 (LIR-1) and LIR-2, (also known as ILT2 and ILT4 respectively) are highly related cell surface, receptors that bind a broad range of class I MHC molecules with low, (microM) affinities. Expressed on monocytic cells and macrophages, both, molecules transmit inhibitory signals after binding ligands. In addition, to binding host class I MHC, the LIR-1 molecule, which is also expressed, on lymphoid tissues, binds with a high (nM) affinity to UL18, a class I, MHC homolog encoded by Human Cytomegalovirus (HCMV). In comparison, LIR-2, binds UL18 only weakly (microM KD). To understand how HCMV preferentially, targets the more broadly expressed LIR-1 molecule, we determined the, crystal structure of a ligand-binding fragment of LIR-2, and compared this, to the existing high-resolution crystal structure of LIR-1. RESULTS:, Recombinant LIR-2 (domains 1 and 2) was produced in E. coli and, crystallized using streak seeding to optimize the crystal morphology. A, data set complete to 1.8 A was collected at 100 K from a single crystal in, the P4(1)2(1)2 spacegroup. The structure was solved by molecular, replacement, using a search model based on the LIR-1 structure., CONCLUSIONS: The overall structure of LIR-2 D1D2 resembles both LIR-1, and, Killer Inhibitory Receptors, in that the A strand in each domain forms, hydrogen bonds to both beta sheets, and there is a sharp angle between the, two immunoglobulin-like domains. However, differences from LIR-1 are, observed in each domain, with two key changes apparent in the, ligand-binding domain, D1. The region corresponding to the residue 44-57, helix of LIR-1 adopts a topology distinct from that of both LIR-1 and the, KIR structures, involving a shortened 310 helix. Secondly, the predicted, UL18 binding region of LIR-1 is altered substantially in LIR-2: the 76-84, loop mainchain is displaced 11 A with respect to LIR-1, and Tyrosine 38, adopts an alternative rotamer conformation. In summary, the structure of, LIR-2 has revealed significant differences to LIR-1, including ones that, may help to explain the &gt;1000-fold lower affinity of LIR-2 for UL18.
+BACKGROUND: Leukocyte Immunoglobulin-like Receptor-1 (LIR-1) and LIR-2 (also known as ILT2 and ILT4 respectively) are highly related cell surface receptors that bind a broad range of class I MHC molecules with low (microM) affinities. Expressed on monocytic cells and macrophages, both molecules transmit inhibitory signals after binding ligands. In addition to binding host class I MHC, the LIR-1 molecule, which is also expressed on lymphoid tissues, binds with a high (nM) affinity to UL18, a class I MHC homolog encoded by Human Cytomegalovirus (HCMV). In comparison, LIR-2 binds UL18 only weakly (microM KD). To understand how HCMV preferentially targets the more broadly expressed LIR-1 molecule, we determined the crystal structure of a ligand-binding fragment of LIR-2, and compared this to the existing high-resolution crystal structure of LIR-1. RESULTS: Recombinant LIR-2 (domains 1 and 2) was produced in E. coli and crystallized using streak seeding to optimize the crystal morphology. A data set complete to 1.8 A was collected at 100 K from a single crystal in the P4(1)2(1)2 spacegroup. The structure was solved by molecular replacement, using a search model based on the LIR-1 structure. CONCLUSIONS: The overall structure of LIR-2 D1D2 resembles both LIR-1, and Killer Inhibitory Receptors, in that the A strand in each domain forms hydrogen bonds to both beta sheets, and there is a sharp angle between the two immunoglobulin-like domains. However, differences from LIR-1 are observed in each domain, with two key changes apparent in the ligand-binding domain, D1. The region corresponding to the residue 44-57 helix of LIR-1 adopts a topology distinct from that of both LIR-1 and the KIR structures, involving a shortened 310 helix. Secondly, the predicted UL18 binding region of LIR-1 is altered substantially in LIR-2: the 76-84 loop mainchain is displaced 11 A with respect to LIR-1, and Tyrosine 38 adopts an alternative rotamer conformation. In summary, the structure of LIR-2 has revealed significant differences to LIR-1, including ones that may help to explain the &gt;1000-fold lower affinity of LIR-2 for UL18.
 ==About this Structure==
-GW5 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with IPA as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2GW5 OCA].
+GW5 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=IPA:'>IPA</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GW5 OCA].
 ==Reference==
@@ Line 14: / Line 13: @@
 [[Category: Homo sapiens]]
 [[Category: Single protein]]
-[[Category: Bjorkman, P.J.]]
+[[Category: Bjorkman, P J.]]
-[[Category: Chapman, T.L.]]
+[[Category: Chapman, T L.]]
-[[Category: Heikema, A.P.]]
+[[Category: Heikema, A P.]]
-[[Category: Thomas, L.M.]]
+[[Category: Thomas, L M.]]
-[[Category: West, A.P.]]
+[[Category: West, A P.]]
-[[Category: Willcox, B.E.]]
+[[Category: Willcox, B E.]]
 [[Category: IPA]]
 [[Category: ig like domains]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 22:23:18 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:35:58 2008''