8ghr
From Proteopedia
Structure of human ENPP1 in complex with variable heavy domain VH27.2
Structural highlights
DiseaseENPP1_HUMAN Defects in ENPP1 are a cause of increased susceptibility for ossification of the posterior longitudinal ligament of the spine (OPLL) [MIM:602475. OPLL is a common form of human myelopathy with a prevalence of as much as 4% in a variety of ethnic groups.[1] Defects in ENPP1 are the cause of arterial calcification of infancy, generalized, type 1 (GACI1) [MIM:208000. A severe autosomal recessive disorder characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. The disorder is often fatal within the first 6 months of life because of myocardial ischemia resulting in refractory heart failure.[2] [3] [4] [5] Defects in ENPP1 are associated with obesity, glucose intolerance, and type II diabetes non-insulin dependent (NIDDM) [MIM:125853.[6] Defects in ENPP1 are the cause of rickets hypophosphatemic autosomal recessive type 2 (ARHR2) [MIM:613312. ARHR2 is a hereditary form of hypophosphatemic rickets, a disorder of proximal renal tubule function that causes phosphate loss, hypophosphatemia and skeletal deformities, including rickets and osteomalacia unresponsive to vitamin D. Symptoms are bone pain, fractures and growth abnormalities.[7] [8] FunctionENPP1_HUMAN Involved primarily in ATP hydrolysis at the plasma membrane. Plays a role in regulating pyrophosphate levels, and functions in bone mineralization and soft tissue calcification. In vitro, has a broad specificity, hydrolyzing other nucleoside 5' triphosphates such as GTP, CTP, TTP and UTP to their corresponding monophosphates with release of pyrophosphate and diadenosine polyphosphates, and also 3',5'-cAMP to AMP. May also be involved in the regulation of the availability of nucleotide sugars in the endoplasmic reticulum and Golgi, and the regulation of purinergic signaling. Appears to modulate insulin sensitivity.[9] IGG1_HUMAN Immunoglobulins, also known as antibodies, are membrane-bound or secreted glycoproteins produced by B lymphocytes. In the recognition phase of humoral immunity, the membrane-bound immunoglobulins serve as receptors which, upon binding of a specific antigen, trigger the clonal expansion and differentiation of B lymphocytes into immunoglobulins-secreting plasma cells. Secreted immunoglobulins mediate the effector phase of humoral immunity, which results in the elimination of bound antigens (PubMed:22158414, PubMed:20176268). The antigen binding site is formed by the variable domain of one heavy chain, together with that of its associated light chain. Thus, each immunoglobulin has two antigen binding sites with remarkable affinity for a particular antigen. The variable domains are assembled by a process called V-(D)-J rearrangement and can then be subjected to somatic hypermutations which, after exposure to antigen and selection, allow affinity maturation for a particular antigen (PubMed:20176268, PubMed:17576170).[10] [11] [12] Publication Abstract from PubMedEctodomain phosphatase/phosphodiesterase-1 (ENPP1) is overexpressed on cancer cells and functions as an innate immune checkpoint by hydrolyzing extracellular cyclic guanosine monophosphate adenosine monophosphate (cGAMP). Biologic inhibitors have not yet been reported and could have substantial therapeutic advantages over current small molecules because they can be recombinantly engineered into multifunctional formats and immunotherapies. Here we used phage and yeast display coupled with in cellulo evolution to generate variable heavy (VH) single-domain antibodies against ENPP1 and discovered a VH domain that allosterically inhibited the hydrolysis of cGAMP and adenosine triphosphate (ATP). We solved a 3.2 A-resolution cryo-electron microscopy structure for the VH inhibitor complexed with ENPP1 that confirmed its new allosteric binding pose. Finally, we engineered the VH domain into multispecific formats and immunotherapies, including a bispecific fusion with an anti-PD-L1 checkpoint inhibitor that showed potent cellular activity. Discovery of VH domains that allosterically inhibit ENPP1.,Solomon PE, Bracken CJ, Carozza JA, Wang H, Young EP, Wellner A, Liu CC, Sweet-Cordero EA, Li L, Wells JA Nat Chem Biol. 2023 Jul 3. doi: 10.1038/s41589-023-01368-5. PMID:37400538[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Homo sapiens | Large Structures | Carozza JA | Li L | Solomon PE | Wang H | Wells JA
