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Springer Lab Crystal Structures
 | ICAM-2
1ZXQ Download
1997 Nature 387:312-315
Casasnovas, J.M., Springer, T.A., Liu, J.-h., Harrison, S.C. and Wang, J.-h.
The crystal structure of ICAM-2 reveals a distinctive integrin recognition surface.
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 | MADCAM-1
1BQS Download
Mucosal Addressin Cell Adhesion Molecule 1
Mucosal addressin cell adhesion molecule 1 (MAdCAM-1) is a
cell adhesion molecule that is expressed on the endothelium in mucosa, and
guides the specific homing of lymphocytes into mucosal tissues. MAdCAM-1
belongs to a subclass of the immunoglobulin superfamily (IgSF), the members
of which are ligands for integrins. Human MAdCAM-1 has a unique dual
function compared to other members in the same subclass in that it binds both
the integrin a4b7, through its two IgSF domains, and a selectin expressed on
leukocytes, via carbohydrate sidechains. The structure determination of the two
IgSF domains and comparison to the N-terminal two-domain structures of
vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion
molecules (ICAM-1 and ICAM-2) allow us to assess the molecular basis of the
interactions between integrins and their preferred ligands.
1998 Structure 6:793-801
Tan, K., Casasnovas, J.M., Liu, J.-h., Briskin, M.J., Springer, T.A. and Wang, J.-h.
The structure of immunoglobulin superfamily domains 1 and 2 of MAdCAM-1 reveals novel features important for integrin recognition.
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 | N-Terminal Two Domains of ICAM-1
1IC1 Download
The 3.0-Å structure of a 190-residue fragment
of intercellular adhesion molecule-1 (ICAM-1, CD54)
reveals two tandem Ig-superfamily (IgSF) domains. Each of
two independent molecules dimerizes identically with a symmetry-
related molecule over a hydrophobic interface on the
BED sheet of domain 1, in agreement with dimerization of
ICAM-1 on the cell surface. The residues that bind to the
integrin LFA-1 are well oriented for bivalent binding in the
dimer, with the critical Glu-34 residues pointing away from
each other on the periphery. Residues that bind to rhinovirus
are in the f lexible BC and FG loops at the tip of domain 1, and
these and the upper half of domain 1 are well exposed in the
dimer for docking to virus. By contrast, a residue important
for binding to Plasmodium falciparum-infected erythrocytes is
in the dimer interface. The presence of A* strands in both
domains 1 and 2, conserved hydrogen bonds at domain
junctions, and elaborate hydrogen bond networks around the
key integrin binding residues in domain 1 make these domains
suited to resist tensile forces during adhesive interactions. A
subdivision of the intermediate (I) set of IgSF domains is
proposed in which domain 1 of ICAM-1 and previously
described I set domains belong to the I1 set and domain 2 of
ICAM-1, ICAM-2, and vascular cell adhesion molecule-1
belong to the I2 set.
1998 Proc Natl Acad Sci USA 95:4134-4139
Casasnovas, J.M., Stehle, T., Liu, J.-h., Wang, J.-h. and Springer, T.A.
A dimeric crystal structure for the N-terminal two domains of ICAM-1.
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 | LDL Receptor YWTD-EGF-Domain Pair
1IJQ Download
The low-density lipoprotein receptor (LDLR) is the primary
mechanism for uptake of cholesterol-carrying particles into
cells. The region of the LDLR implicated in receptor recycling
and lipoprotein release at low pH contains a pair of calciumbinding
EGF-like modules, followed by a series of six YWTD
repeats and a third EGF-like module. The crystal structure at
1.5 Å resolution of a receptor fragment spanning the YWTD
repeats and its two flanking EGF modules reveals that the
YWTD repeats form a six-bladed β-propeller that packs
tightly against the C-terminal EGF module, whereas the EGF
module that precedes the propeller is disordered in the crystal.
Numerous point mutations of the LDLR that result in the
genetic disease familial hypercholesterolemia (FH) alter side
chains that form conserved packing and hydrogen bonding
interactions in the interior and between propeller blades. A
second subset of FH mutations are located at the interface
between the propeller and the C-terminal EGF module, suggesting
a structural requirement for maintaining the integrity
of the interdomain interface.
2001 Nat Struc Biol 8:499-504
Jeon, H., Meng, W., Takagi, J., Eck, M.J., Springer, T.A. and Blacklow, S.C.
Implications for familial hypercholesterolemia from structure of the LDL receptor YWTD-EGF domain pair.
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 | Tandem YVTN Beta-Propeller and PKD Domains
1L0Q Download
The surface layer of archaeobacteria protects cells from extreme environments and, in Methanosarcina,may regulate cell adhesion. We identify three domain types
that account for the complete architecture of numerous Methanosarcina surface layer proteins.
2002 Structure 10: 1453-1464
Jing, H., Takagi, J., Liu, J-h., Lindgren, S., Zhang, R-G., Joachimiak, A., Wang, J-h., andSpringer, T. A.
Archaeal surface layer proteins contain b-propeller, polycystic kidney disease, and b-helix domains, and are related to metazoan cell surface proteins.
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 | Integrin EGF-like Module 3 from the Beta 2 Subunit
1L3Y Download
Cysteine-rich module structure reveals a fulcrum for inegrin rearrangement upon activation.
2002 Nat Struct Biol 9: 282-287
Beglova, N., Blacklow, S.C., Takagi, J., and Springer, T.A.
Cysteine-rich module structure reveals a fulcrum for integrin rearrangement upon activation.
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 | Intermediate Affinity alpha-L I domain mutant
1MJN Download
The structure of the I domain of integrin alpha-L beta-2 bound to the Ig superfamily ligand ICAM-1 reveals the open ligand binding conformation and the first example of an integrin-IgSF interface.
2003 Cell 112: 99-111
Shimaoka, M., Xiao, T., Liu, J-H., Yang, Y., Dong, Y., Jun, C-D., McCormack, A., Zhang, R.,Joachimiak, A., Takagi, J., Wang, J-H., and Springer, T.A.
Structures of the aL I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation.
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 | alpha-L I domain in complex with ICAM-1
1MQ8 Download
The structure of the I domain of integrin alpha-L beta-2 bound to the Ig superfamily ligand ICAM-1 reveals the open ligand binding conformation and the first example of an integrin-IgSF interface.
2003 Cell 112: 99-111
Shimaoka, M., Xiao, T., Liu, J-H., Yang, Y., Dong, Y., Jun, C-D., McCormack, A., Zhang, R.,Joachimiak, A., Takagi, J., Wang, J-H., and Springer, T.A.
Structures of the aL I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation.
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 | High Affinity alpha-L I domain with ligand mimetic crystal contact
1MQ9 Download
2003 Cell 112: 99-111
Shimaoka, M., Xiao, T., Liu, J-H., Yang, Y., Dong, Y., Jun, C-D., McCormack, A., Zhang, R.,Joachimiak, A., Takagi, J., Wang, J-H., and Springer, T.A.
Structures of the aL I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation.
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 | alpha-L I domain without ligand or metal
1MQA Download
2003 Cell 112: 99-111
Shimaoka, M., Xiao, T., Liu, J-H., Yang, Y., Dong, Y., Jun, C-D., McCormack, A., Zhang, R.,Joachimiak, A., Takagi, J., Wang, J-H., and Springer, T.A.
Structures of the aL I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation.
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 | alpha-X integrin I domain
1NY3 Download
The integrin X2 (CD11cCD18, p150,95) binds ligands through
the I domain of the X subunit. Ligands include the complement
factor fragment iC3b, a key component in the innate immune
defense, which, together with the expression of X2 on dendritic
cells and on other leukocytes, suggests a role in the immune
response. We now report the structure of the X I domain resolved
at 1.65 Å by x-ray crystallography. To analyze structural requirements
for ligand binding we made a mutation in the X I domain
C-terminal helix, which increased the affinity for iC3b 200-fold to
2.4 M compared with the wild-type domain affinity of 400 M.
Gel permeation chromatography supported a conformational
change between the wild-type and mutated domains. Conservation
of allosteric regulation in the X I domain points to the
functional importance of this phenomenon.
2003 Proc Natl Acad Sci USA 100: 1873-1878
Vorup-Jensen, T., Shimaoka, M., Ostermeier, C., Hommel, U., and Springer, T.A.
Structure and allosteric regulation of the aXb2 integrin I domain.
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 | Nidogen/Laminin Complex
1NPE Download
Basement membranes are fundamental to tissue organization
and physiology in all metazoans. The interaction between laminin
and nidogen is crucial to the assembly of basement membranes1–
4. The structure of the interacting domains reveals a sixbladed
Tyr-Trp-Thr-Asp (YWTD) b-propeller domain in nidogen
bound to laminin epidermal-growth-factor-like (LE) modules
III3–5 in laminin (LE3–5). Laminin LE module 4 binds to an
amphitheatre-shaped surface on the pseudo-6-fold axis of the
b-propeller, and LE module 3 binds over its rim. A Phe residue
that shutters the water-filled central aperture of the b-propeller,
the rigidity of the amphitheatre, and high shape complementarity
enable the construction of an evolutionarily conserved
binding surface for LE4 of unprecedentedly high affinity for its
small size5. Hypermorphic mutations in the Wnt co-receptor
LRP5 suggest that a similar YWTD b-propeller
interface is used to bind ligands that function in developmental
pathways. A related interface, but shifted off-centre from the
pseudo-6-fold axis and lacking the shutter over the central
aperture, is used in the low-density lipoprotein receptor for an
intramolecular interaction that is regulated by pH in receptor
recycling.
2003 Nature 424: 969-974 Supplementary Info: S1, S2,
Takagi, J., Yang, Y., Liu, J-h., Wang, J-h., and Springer, T. A.
Complex between nidogen and laminin fragments reveals a paradigmatic b-propeller interface.
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 | ICAM-1 D3-D5 fragment
1P53 Download
Combined with the previously known N-terminal two-domain structure (D1D2), a model of an entire ICAM-1 extracellular
fragment has been constructed.
2004 Mol Cell 14: 269-276
Yang Y, Jun C-D, Liu J-h, Zhang R-G, Jochimiak A, Springer, T.A., Wang, J-h.
Structural basis for dimerization of ICAM-1 on the cell surface.
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 | Complex of ICAM-3 and alpha-L beta-2 binding domains
1T0P Download
Within the Ig superfamily (IgSF), intercellular adhesion molecules
(ICAMs) form a subfamily that binds the leukocyte integrin L2.
We report a 1.65-Å-resolution crystal structure of the ICAM-3
N-terminal domain (D1) in complex with the inserted domain, the
ligand-binding domain of L2. This high-resolution structure and
comparisons among ICAM subfamily members establish that the
binding of ICAM-3 D1 onto the inserted domain represents a
common docking mode for ICAM subfamily members. The markedly
different off-rates of ICAM-1, -2, and -3 appear to be determined
by the hydrophobicity of residues that surround a metal
coordination bond in the L2-binding interfaces. Variation in
composition of glycans on the periphery of the interfaces influences
on-rate.
2005 Proc Natl Acad Sci USA 102: 3366-3371
Song, G., Yang, Y., Liu, J.-h., Casasnovas, J., Shimaoka, M., Springer, T. A., and Wang,J. -h.
An atomic resolution view of ICAM recognition in a complex between the binding domains of ICAM-3 and integrin aLb2.
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 | alpha II b beta-3 with mAb 10E5
1TXV Download
Here, we define
with crystal structures the atomic basis for allosteric regulation of the conformation and affinity for ligand of the integrin
ectodomain, and how fibrinogen-mimetic therapeutics bind to platelet integrin aIIbb3. Allostery in the b3 I domain alters three metal
binding sites, associated loops and a1- and a7-helices. Piston-like displacement of the a7-helix causes a 628 reorientation
between the b3 I and hybrid domains. Transmission through the rigidly connected plexin/semaphorin/integrin (PSI) domain in the
upper b3 leg causes a 70A°
separation between the knees of the a and b legs. Allostery in the head thus disrupts interaction
between the legs in a previously described low-affinity bent integrin conformation, and leg extension positions the high-affinity
head far above the cell surface.
2004 Nature 432: 59-67. Supplementary Info: S1, S2,
Xiao T, Takagi J, Wang J-h, Coller BS, Springer TA.
Structural basis for allostery in integrins and binding of ligand-mimetic therapeutics to the platelet receptor for fibrinogen.
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 | alpha II b beta-3 with antibody 10E5 with drug Eptifibatide
1TY6 Download
2004 Nature 432: 59-67. Supplementary Info: S1, S2,
Xiao T, Takagi J, Wang J-h, Coller BS, Springer TA.
Structural basis for allostery in integrins and binding of ligand-mimetic therapeutics to the platelet receptor for fibrinogen.
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 | alpha II b beta-3 with antibody 10E5 with drug L739758
1TY7 Download
2004 Nature 432: 59-67. Supplementary Info: S1, S2,
Xiao T, Takagi J, Wang J-h, Coller BS, Springer TA.
Structural basis for allostery in integrins and binding of ligand-mimetic therapeutics to the platelet receptor for fibrinogen.
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 | Re-refinement of Integrin alpha II b beta-3 Headpiece
2VDK Download
previous version: 1TY3
2008 J. Cell Biol. 182, 791-800
Springer, T.A., Zhu, J., Xiao, T.
Structural basis for distinctive recognition of fibrinogen by the platelet integrin αIIbβ3
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 | Re-refinement of Integrin alpha II b beta-3 Headpiece
2VDL Download
previous version: 1TXV
2008 J. Cell Biol. 182, 791-800
Springer, T.A., Zhu, J., Xiao, T.
Structural basis for distinctive recognition of fibrinogen by the platelet integrin αIIbβ3
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 | Re-refinement of Integrin alpha II b beta-3 Headpiece with Tirofiban
2VDM Download
previous version: 1TY5
2008 J. Cell Biol. 182, 791-800
Springer, T.A., Zhu, J., Xiao, T.
Structural basis for distinctive recognition of fibrinogen by the platelet integrin αIIbβ3
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 | Re-refinement of Integrin alpha II b beta-3 Headpiece with Eptifibatide
2VDN Download
previous version: 1TY6
2008 J. Cell Biol. 182, 791-800
Springer, T.A., Zhu, J., Xiao, T.
Structural basis for distinctive recognition of fibrinogen by the platelet integrin αIIbβ3
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 | Re-refinement of Integrin alpha II b beta-3 Headpiece with L-739758
2VC2 Download
previous version: 1TY7
2008 J. Cell Biol. 182, 791-800
Springer, T.A., Zhu, J., Xiao, T.
Structural basis for distinctive recognition of fibrinogen by the platelet integrin αIIbβ3
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