Target Information
| Target General Information | Top | |||||
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| Target ID |
T35640
(Former ID: TTDS00444)
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| Target Name |
Integrin alpha-L (ITGAL)
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| Synonyms |
Lymphocyte Function-associated Antigen-1; Leukocyte function-associated molecule 1 alpha chain; Leukocyte function associated molecule 1, alpha chain; Leukocyte adhesion glycoprotein LFA-1 alpha chain; LFA-1A; LFA-1; CD11a; CD11 antigen-like family member A
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| Gene Name |
ITGAL
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Psoriasis [ICD-11: EA90] | |||||
| 2 | Visual system disease [ICD-11: 9E1Z] | |||||
| Function |
Integrin ITGAL/ITGB2 is a receptor for F11R. Integin ITGAL/ITGB2 is a receptor for the secreted form of ubiquitin-like protein ISG15; the interaction is mediated by ITGAL. Involved in a variety of immune phenomena including leukocyte-endothelial cell interaction, cytotoxic T-cell mediated killing, and antibody dependent killing by granulocytes and monocytes. Contributes to natural killer cell cytotoxicity. Involved in leukocyte adhesion and transmigration of leukocytes including T-cells and neutrophils. Required for generation of common lymphoid progenitor cells in bone marrow, indicating a role in lymphopoiesis. Integrin ITGAL/ITGB2 in association with ICAM3, contributes to apoptotic neutrophil phagocytosis by macrophages. Integrin ITGAL/ITGB2 is a receptor for ICAM1, ICAM2, ICAM3 and ICAM4.
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| BioChemical Class |
Integrin
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| UniProt ID | ||||||
| Sequence |
MKDSCITVMAMALLSGFFFFAPASSYNLDVRGARSFSPPRAGRHFGYRVLQVGNGVIVGA
PGEGNSTGSLYQCQSGTGHCLPVTLRGSNYTSKYLGMTLATDPTDGSILACDPGLSRTCD QNTYLSGLCYLFRQNLQGPMLQGRPGFQECIKGNVDLVFLFDGSMSLQPDEFQKILDFMK DVMKKLSNTSYQFAAVQFSTSYKTEFDFSDYVKRKDPDALLKHVKHMLLLTNTFGAINYV ATEVFREELGARPDATKVLIIITDGEATDSGNIDAAKDIIRYIIGIGKHFQTKESQETLH KFASKPASEFVKILDTFEKLKDLFTELQKKIYVIEGTSKQDLTSFNMELSSSGISADLSR GHAVVGAVGAKDWAGGFLDLKADLQDDTFIGNEPLTPEVRAGYLGYTVTWLPSRQKTSLL ASGAPRYQHMGRVLLFQEPQGGGHWSQVQTIHGTQIGSYFGGELCGVDVDQDGETELLLI GAPLFYGEQRGGRVFIYQRRQLGFEEVSELQGDPGYPLGRFGEAITALTDINGDGLVDVA VGAPLEEQGAVYIFNGRHGGLSPQPSQRIEGTQVLSGIQWFGRSIHGVKDLEGDGLADVA VGAESQMIVLSSRPVVDMVTLMSFSPAEIPVHEVECSYSTSNKMKEGVNITICFQIKSLI PQFQGRLVANLTYTLQLDGHRTRRRGLFPGGRHELRRNIAVTTSMSCTDFSFHFPVCVQD LISPINVSLNFSLWEEEGTPRDQRAQGKDIPPILRPSLHSETWEIPFEKNCGEDKKCEAN LRVSFSPARSRALRLTAFASLSVELSLSNLEEDAYWVQLDLHFPPGLSFRKVEMLKPHSQ IPVSCEELPEESRLLSRALSCNVSSPIFKAGHSVALQMMFNTLVNSSWGDSVELHANVTC NNEDSDLLEDNSATTIIPILYPINILIQDQEDSTLYVSFTPKGPKIHQVKHMYQVRIQPS IHDHNIPTLEAVVGVPQPPSEGPITHQWSVQMEPPVPCHYEDLERLPDAAEPCLPGALFR CPVVFRQEILVQVIGTLELVGEIEASSMFSLCSSLSISFNSSKHFHLYGSNASLAQVVMK VDVVYEKQMLYLYVLSGIGGLLLLLLIFIVLYKVGFFKRNLKEKMEAGRGVPNGIPAEDS EQLASGQEAGDPGCLKPLHEKDSESGGGKD Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T91F6Z | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 2 Approved Drugs | + | ||||
| 1 | Efalizumab | Drug Info | Approved | Psoriasis vulgaris | [2], [3] | |
| 2 | lifitegrast | Drug Info | Approved | Dry eye disease | [4] | |
| Discontinued Drug(s) | [+] 2 Discontinued Drugs | + | ||||
| 1 | BMS-587101 | Drug Info | Discontinued in Phase 2 | Psoriasis vulgaris | [5] | |
| 2 | IC-747 | Drug Info | Discontinued in Phase 2 | Psoriasis vulgaris | [6] | |
| Preclinical Drug(s) | [+] 1 Preclinical Drugs | + | ||||
| 1 | Cytolin | Drug Info | Preclinical | Human immunodeficiency virus infection | [7] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Modulator | [+] 2 Modulator drugs | + | ||||
| 1 | lifitegrast | Drug Info | [1], [4] | |||
| 2 | Leukotoxin | Drug Info | [13] | |||
| Inhibitor | [+] 3 Inhibitor drugs | + | ||||
| 1 | BMS-587101 | Drug Info | [9] | |||
| 2 | A-286982 | Drug Info | [12] | |||
| 3 | LFA703 | Drug Info | [14] | |||
| Antagonist | [+] 1 Antagonist drugs | + | ||||
| 1 | IC-747 | Drug Info | [10] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Lovastatin | Ligand Info | |||||
| Structure Description | X-ray structure of Lfa-1 I domain in complex with Lovastatin collected at 273 K | PDB:7KC6 | ||||
| Method | X-ray diffraction | Resolution | 1.85 Å | Mutation | No | [15] |
| PDB Sequence |
GSGNVDLVFL
135 FDGSMSLQPD145 EFQKILDFMK155 DVMKKLSNTS165 YQFAAVQFST175 SYKTEFDFSD 185 YVKRKDPDAL195 LKHVKHMLLL205 TNTFGAINYV215 ATEVFREELG225 ARPDATKVLI 235 IITDGEATDS245 GNIDAAKDII255 RYIIGIGKHF265 QTKESQETLH275 KFASKPASEF 285 VKILDTFEKL295 KDLFTELQKK305 IYVI
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VAL130
3.782
LEU132
2.339
PHE134
4.278
PHE153
2.403
VAL157
2.962
LEU161
3.638
TYR166
3.237
PHE168
4.841
THR231
4.814
VAL233
2.475
ILE235
2.318
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Isoflurane | Ligand Info | |||||
| Structure Description | Crystal structure of wild type LFA1 I domain complexed with isoflurane | PDB:3F78 | ||||
| Method | X-ray diffraction | Resolution | 1.60 Å | Mutation | Yes | [16] |
| PDB Sequence |
GNVDLVFLFD
137 GSMSLQPDEF147 QKILDFMKDV157 MKKLSNTSYQ167 FAAVQFSTSY177 KTEFDFSDYV 187 KWKDPDALLK197 HVKHMLLLTN207 TFGAINYVAT217 EVFREELGAR227 PDATKVLIII 237 TDGEATDSGN247 IDAAKDIIRY257 IIGIGKHFQT267 KESQETLHKF277 ASKPASEFVK 287 ILDTFEKLKD297 LFTELQKKIY307
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Rap1 signaling pathway | hsa04015 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Cell adhesion molecules | hsa04514 | Affiliated Target |
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| Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
| Neutrophil extracellular trap formation | hsa04613 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Natural killer cell mediated cytotoxicity | hsa04650 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Leukocyte transendothelial migration | hsa04670 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Regulation of actin cytoskeleton | hsa04810 | Affiliated Target |
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| Class: Cellular Processes => Cell motility | Pathway Hierarchy | ||
| Click to Show/Hide the Information of Affiliated Human Pathways | |||
| Degree | 15 | Degree centrality | 1.61E-03 | Betweenness centrality | 2.20E-04 |
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| Closeness centrality | 2.11E-01 | Radiality | 1.37E+01 | Clustering coefficient | 1.14E-01 |
| Neighborhood connectivity | 2.00E+01 | Topological coefficient | 1.20E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Corneal inflammation is inhibited by the LFA-1 antagonist, lifitegrast (SAR 1118). J Ocul Pharmacol Ther. 2013 May;29(4):395-402. | |||||
| REF 2 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6593). | |||||
| REF 3 | New developments in immunosuppressive therapy for heart transplantation. Expert Opin Emerg Drugs. 2009 Mar;14(1):1-21. | |||||
| REF 4 | 2016 FDA drug approvals. Nat Rev Drug Discov. 2017 Feb 2;16(2):73-76. | |||||
| REF 5 | Small molecules, big targets: drug discovery faces the protein-protein interaction challenge.Nat Rev Drug Discov. 2016 Aug;15(8):533-50. | |||||
| REF 6 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015378) | |||||
| REF 7 | Clinical pipeline report, company report or official report of CytoDyn Inc. | |||||
| REF 8 | [Successful therapy of discoid lupus erythematosus with efalizumab]. Hautarzt. 2010 Mar;61(3):246-9. | |||||
| REF 9 | Small molecule antagonist of leukocyte function associated antigen-1 (LFA-1): structure-activity relationships leading to the identification of 6-(... J Med Chem. 2010 May 13;53(9):3814-30. | |||||
| REF 10 | HECA-452+ T Cells Migrate Through Superficial Vascular Plexus but Not Through Deep Vascular Plexus Endothelium. Journal of Investigative Dermatology. 04/1997; 108(3):343-8. | |||||
| REF 11 | Cytokine-induced phagocyte adhesion to human mesangial cells: role of CD11/CD18 integrins and ICAM-1. Am J Physiol. 1991 Dec;261(6 Pt 2):F1071-9. | |||||
| REF 12 | Discovery of tetrahydroisoquinoline (THIQ) derivatives as potent and orally bioavailable LFA-1/ICAM-1 antagonists. Bioorg Med Chem Lett. 2010 Sep 1;20(17):5269-73. | |||||
| REF 13 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2451). | |||||
| REF 14 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 15 | Divergent conformational dynamics controls allosteric ligand accessibility across evolutionarily related I-domain-containing integrins | |||||
| REF 16 | Crystal structure of isoflurane bound to integrin LFA-1 supports a unified mechanism of volatile anesthetic action in the immune and central nervous systems. FASEB J. 2009 Aug;23(8):2735-40. | |||||
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